Antiatherosclerotic ureas and thioureas

ABSTRACT

This invention is concerned with ureas and thioureas which may be represented by the formula: ##STR1## wherein X represents at least one substituent selected from the group consisting of (C 1  -C 4 )alkyl, (C 1  -C 4 )alkenyl, (C 1  -C 4 )alkynyl, phenoxy, mercapto, amino, (C 1  -C 4 )alkylamino, di-(C 1  -C 4 )alkylamino, halo, trihalomethyl, (C 1  -C 4 )alkanoyl), benzoyl, (C 1  -C 4 )alkanamido, haloacetamido, nitro, cyano, carboxy, (C 1  -C 4 )carboalkoxy, carbamoyl, sulfamyl, methylenedioxy, phenyl, orthophenylene, tolyl, benzyl, halobenzyl, methylbenzyl; Y is selected from the group consisting of oxygen and sulfur; R 1  and R 2  are different and are independently selected from the group consisting of (C 4  -C 12 )alkyl, (C 4  -C 12 )alkenyl, (C 4  -C 12 )alkynyl, (C 4  -C 12 )cycloalkylalkyl, (C 7  -C 14 )aralkyl, and (C 7  -C 14 )aralkyl in which an aromatic ring bears at least one substituent selected from the group consisting of (C 1  -C 10 )alkyl, (C 1  -C 10 )alkoxy, phenoxy, benzyloxy, methylenedioxy, (C 1  -C 14 )alkylthio, phenyl, halo, trihalomethyl, adamantyl, (C 1  -C 4 )carboalkoxy, and nitro.

BACKGROUND OF THE INVENTION

This application is a continuation-in-part of my copending applicationSer. No. 515,321, filed July 19, 1983, now abandoned, which in turn is acontinuation-in-part of my abandoned application Ser. No. 342,692, filedJan. 26, 1982, now abandoned.

This invention relates to new urea and thiourea compounds useful aspharmaceutical agents. The novel compounds of the present invention areantiatherosclerotic agents capable of ameliorating atherosclerosis bycounteracting the formation or development of antheromatous lesions inthe arterial wall of mammals. The invention also relates to the chemicalsynthesis of the novel compounds disclosed herein. In addition, theinvention pertains to novel pharmaceutical compositions for theutilization of these compounds in the treatment of disease in mammals.Further, the invention contemplates methods for treating atherosclerosisin a manner designed to prevent, arrest, or reverse the course of thedisease.

A variety of urea and thiourea compounds can be found in the literature,for example, in J. Med. Chem., 18: 1024 (1975); Chem. Absts., 95: 6758m(1981) and 91: 74631g (1979); U.S. Pat. Nos. 2,688,039; 3,335,142;3,856,952; 3,903,130; 4,252,957; 4,405,644; and 4,460,607. The compoundsfound in the literature are disclosed as being useful herbicides, plantgrowth regulators, bactericides, pesticides, fungicides, algacides,photographic sensitizers, antihelmintics, sympatholytics, andantivirals. Those urea compounds found in U.S. Pat. Nos. 4,405,644 and4,460,607 are disclosed as useful in inhibiting lipid absorption. Thereare, however, no literature references disclosing the urea and thioureacompounds of the present invention or their use in the treatment ofatherosclerosis or hyperlipidemia.

Atherosclerosis is a form of arteriosclerosis characterized by lipidaccumulation in and thickening of the arterial walls of both medium- andlarge-sized arteries. Arterial walls are thereby weakened, and theelasticity and effective internal size of the artery is decreased.Atherosclerosis is the most common cause of ischemic heart disease andis of great medical importance since the occlusion of medium- andlarge-sized arteries diminishes the supply of blood to vital organs suchas the heart muscles and the brain. The sequelae to atherosclerosisinclude ischemic heart disease, heart failure, life-threateningarrythmias, senility, and stroke.

The fact that cholesterol is a major component of atheroscleroticlesions or plaques has been known for more than 100 years. Variousresearchers have studied the role of cholesterol in lesion formation anddevelopment and also, more importantly, whether lesion formation can beprevented or lesion development arrested or reversed. Atheromatouslesions have now been shown [Adams, et al., Atherosclerosis, 13: 429(1974)] to contain a greater quantity of esterified as opposed tounesterified cholesterol than the surrounding undiseased arterial wall.The intracellular esterification of cholesterol with fatty acids iscatalyzed by the enzyme Fatty acyl CoA: chloesterol acyl transferase orACAT, and the accumulation and storage of cholesteryl esters in thearterial wall is associated with increased activity of this enzyme[Hashimoto and Dayton, Atheroscelerosis, 28: 447 (1977)]. In addition,cholesteryl esters are removed from cells at a slower rate thanunesterified cholesterol [Bondjers and Bjorkerud, Atherosclerosis, 15:273 (1972) and 22: 379 (1975)]. Thus, inhibition of the ACAT enzymewould diminish the rate of cholesterol esterification, decrease theaccumulation and storage of cholesteryl esters in the arterial wall, andprevent or inhibit the formation and development of atheromatouslesions. The compounds of the present invention are very potentinhibitors of the ACAT enzyme. Thus, these compounds are useful forcontrolling and reducing the cholesteryl ester content of mammalianarterial walls and decreasing the accumulation and storage ofcholesterol in the arterial walls of mammals. Further, the compounds ofthis invention inhibit the formation or development of atheroscleroticlesions in mammals.

The evidence that hyperlipidemia is one of the factors involved incoronary heart disease is very impressive. A most important studycarried out in Framingham, Mass. in over 5,000 persons for more than 12years established a correlation between high concentrations of bloodcholesterol and increased risk of heart attack. Although the causes ofcoronary artery disease are multiple, one of the most constant factorshas been the elevated concentration of lipids in the blood plasma. Acombined elevation of cholesterol and triglycerides has been shown tocarry the highest risk of coronary heart disease. The majority ofpatients with ischemic heart disease or peripheral vascular disease werefound to have hyperlipoproteinemia, involving very low-density and/orlow-density lipoproteins.

I have now found that certain members of this class of compounds cansafely and effectively lower serum lipids in warm-blooded animals. Suchaction on serum lipids is considered to be very useful in the treatmentof atherosclerosis. For some time, it has been considered desirable tolower serum-lipid levels and to correct lipoprotein imbalance in mammalsas a preventive measure against atherosclerosis. The compounds of thepresent invention do not act by blocking late stages of cholesterolbiosynthesis and thus do not produce accumulation of intermediates suchas desmosterol, as equally undesirable as cholesterol itself. Compoundswith the combination of therapeutically favorable characteristicspossessed by those of the present invention can be safely administeredto warm-blooded mammals for the treatment of hyperlipidemic andatherosclerotic states found in patients with or prone to heart attacks,to peripheral or cerebral vascular disease, and to stroke.

The compounds of this invention exhibit anti-atherosclerotic activity,and the invention should not be construed as limited to any particularmechanism of anti-atherosclerotic action.

SUMMARY OF THE INVENTION

This invention relates to new urea and thiourea compounds, theirpreparation, pharmaceutical compositions containing them, and their usein the treatment of atherosclerosis. More particularly, it isgenerically concerned with ureas and thioureas which may be representedby Formula I: ##STR2## wherein X represents at least one substituentselected from the group consisting of (C₁ -C₄)alkyl, (C₁ -C₄)alkenyl,(C₁ -C₄)alkynyl, phenoxy, mercapto, amino, (C₁ -C₄)alkylamino, di-(C₁-C₄)alkylamino, halo, trihalomethyl, (C₁ -C₄)alkanoyl, benzoyl, (C₁-C₄)alkanamido, haloacetamido, nitro, cyano, carboxy, (C₁-C₄)carboalkoxy, carbomyl, sulfamyl, methylenedioxy, phenyl,orthophenylene, tolyl, benzyl, halobenzyl, methylbenzyl, and the group:##STR3## Y is selected from the group consisting of oxygen and sulfur;R₁ is selected from the group consisting of (C₄ -C₁₂)alkyl, (C₄-C₁₂)alkenyl, (C₄ -C₁₂)alkynyl, (C₄ -C₁₂)cycloalkylalkyl, (C₇-C₁₄)aralkyl, and (C₇ -C₁₄)aralkyl in which an aromatic ring bears atleast one substituent selected from the group consisting of (C₁-C₁₀)alkyl, (C₁ -C₁₀)alkoxy, phenoxy, benzyloxy, methylenedioxy, (C₁-C₄)alkylthio, phenyl, halo, trihalomethyl, adamantyl, (C₁-C₄)carboalkoxy, and nitro; and R₂ is not identical to R¹ and isselected from the group consisting of (C₄ -C₁₂)alkyl, (C₄ -C₁₂)alkenyl,(C₄ -C₁₂)alkynyl, (C₄ -C₁₂)cycloalkylalkyl, (C₇ -C₁₄)aralkyl, and (C₇-C₁₄)aralkyl in which an aromatic ring bears at least one substituentselected from the group consisting of (C₁ -C₁₀)alkyl, (C₁ -C₁₀)alkoxy,phenoxy, benzyloxy, methylenedioxy, (C₁ -C.sub. 4)alkylthio, phenyl,halo, trihalomethyl, adamantyl, (C₁ -C₄)carboalkoxy, nitro, and A-Zwherein A is selected from the group consisting of (C₂ -C₁₀)alkylene,(C₂ -C₁₀)alkenylene, and (C₂ -C₁₀)alkynylene and Z is selected from thegroup consisting of carboxy, (C₁ -C₄)carboalkoxy, carbamoyl, (C₁-C₄)perfluoroalkyl, (tri(C₁ -C₄)alkyl)silyl, cyano, halo, mercapto, (C₁-C₄)alkylthio, hydroxy, (C₁ -C₄)alkoxy, methylsulfonyloxy, (C₁-C₄)alkoxy, thienyl, furyl, and pyrimidinyl.

A preferred subgeneric group of ureas and thioureas with which thisinvention is concerned may be represented by Formula II: ##STR4##wherein X represents at least one substitutent selected from the groupconsisting of (C₁ -C₄)alkyl, (C₁ -C₄)alkenyl, (C₁ -C₄)alkynyl, phenoxy,mercapto, amino, (C₁ -C₄)alkylamino, di-(C₁ -C₄)alkylamino, halo,trihalomethyl, (C₁ -C₄)alkanoyl, benzoyl, (C₁ -C₄)alkanamido,haloacetamido, nitro, cyano, carboxy, (C₁ -C₄)carboalkoxy, carbamoyl,sulfamyl, methylenedioxy, phenyl, orthophenylene, tolyl, benzyl,halobenzyl, methylbenzyl; Y is selected from the group consisting ofoxygen and sulfur; R₁ and R₂ are different and are independentlyselected from the group consisting of (C₄ -C₁₂)alkyl, (C₄ -C₁₂)alkenyl,(C₄ -C₁₂)alkynyl, (C₄ -C₁₂)cycloalkylalkyl, (C₇ -C₁₄)aralkyl, and (C₇-C₁₄)aralkyl in which an aromatic ring bears at least one substituentselected from the group consisting of (C₁ -C₁₀)alkyl, (C₁ -C₁₀)alkoxy,phenoxy, benzyloxy, methylenedioxy, (C₁ -C₄)alkylthio, phenyl, halo,trihalomethyl, adamantyl, (C₁ -C₄)carboalkoxy, and nitro.

Preferred embodiments of the invention represented by Formula II arethose in which Y is oxygen. More preferred are those in which Xrepresents at least one (C₁ -C₄)alkyl or halo substituent, R₁ is (C₇-C₁₄)aralkyl or substituted (C₇ -C₁₄)aralkyl, and R₂ is (C₄ -C₁₂)alkyl.The most preferred are those in which X represents at least one methyl,chloro, or fluoro substituent.

Preferred specific embodiments involve trisubstituted ureas, forexample:

1-Benzyl-1-(n-butyl)-3-(2,4-dimethylphenyl)urea

1Benzyl-1-(1,2-diphenylethyl)-3-(2,4-dimethylphenyl)urea

1-(2-Fluorobenzyl)-1-(2-methoxybenzyl)-3-(2,4-dimethylphenyl)urea

1-(n-Butyl)-1-(4-hexyloxybenzyl)-3-(2,4-dimethylphenyl)urea

1-Benzyl-1(4-n-butylbenzyl)-3-(2,4-dimethylphenyl)urea

1-Benzyl-1-(4-n-butylbenzyl)-3-(2,4,6-trimethylphenyl)urea

1-(n-Heptyl)-1-(4-n-butylbenzyl)-3-(2,4-dimethylphenyl)urea

1-(n-Heptyl)-1-(4-n-butylbenzyl)-3-(2,4,5-trimethylphenyl)urea

1-(n-Heptyl)-1-(4-butyloxybenzyl)-3-(2,4-dimethylphenyl)urea

1-(n-Heptyl)-1-(4-butyloxybenzyl)-3-(2,4,5-trimethylphenyl)urea

1-Benzyl-1-(4-butyloxybenzyl)-3-(2,4-dimethylphenyl)urea

1-Benzyl-1-(4butyloxybenzyl)-3-(2,4,5-trimethylphenyl)urea

1-Benzyl-1-(4-n-butylbenzyl)-3-(2,4,5-trimethylphenyl)urea

1-(n-Heptyl)-1-(4-n-butoxybenzyl)-3-(2,4,6-trichlorophenyl)urea

1-Benzyl-1-(4-n-butoxybenzyl)-3-(2,4,6-trichlorophenyl)urea

1-(n-Heptyl)-1-(4-n-butylbenzyl)-3-(2,4,6-trichlorophenyl)urea

1-Benzyl-1-(4-n-butylbenzyl)-3-(2-methyl-4-chlorophenyl)urea

1-(n-Heptyl)-1-(4-n-butoxybenzyl)-3-(2,4-difluorophenyl)urea

1-(n-Heptyl)-1-(4-n-butoxybenzyl)-3-(2-methyl-4-chlorophenyl)urea

1-(n-Heptyl)-1-(4-n-butylbenzyl)-3-(2-methyl-4-chlorophenyl)urea

1-(n-Heptyl)-1-(4-n-butylbenzyl)-3-(2,4-difluorophenyl)urea

1-(n-Heptyl)-1-(4-n-butylbenzyl)-3-(2-methylphenyl)urea

1-(n-Heptyl)-1-(2-phenylethyl)-3-(2,4-dimethylphenyl)urea

1-(4-Chlorobenzyl)-1-(1-naphthylmethyl)-3-(2,4,6-trichlorophenyl)urea

1-(4-Chlorobenzyl)-1-(1-naphthylmethyl)-3-(2-methyl-4-chlorophenyl)urea

1-(4-Chlorobenzyl)-1-(1-naphthylmethyl)-3-(2,4-difluorophenyl)urea

1-Benzyl-1-[2-phenyl-1-(4-benzyloxyphenyl)ethyl]-3-(2,4-difluorophenyl)urea

1-Benzyl-1-(4-n-butoxybenzyl)-3-(2,4-difluorophenyl)urea

1-(2-Furanylmethyl)-1-heptyl-3-(2,4,5-trimethylphenyl)urea

1-(2-Furanylmethyl)-1-heptyl-3-(2,4,6-trichlorophenyl)urea

1-Heptyl-1-(2-thienylmethyl)-3-(2,4,5-trimethylphenyl)urea

1-Heptyl-1-(2-thienylmethyl)-3-(2,4,6-trichlorophenyl)urea

1-[(4-Butoxyphenyl)methyl]-1-(2-thienylmethyl)-3-(2,4,5-trimethylphenyl)urea

1-[(4-Butylphenyl)methyl]-1-(6-cyanohexyl)-3-(2,4,5-trimethylphenyl)urea

1-[(4-Butylphenyl)methyl]-1-(6-chlorohexyl)-3-(2,4,5-trimethylphenyl)urea

1-[(4-Butylphenyl)methyl]-1-(6-chlorohexyl)-3-(4-chloro-2-methylphenyl)urea

1-[(4-Butylphenyl)methyl]-1-(6-hydroxyhexyl)-3-(2,4,6-trichlorophenyl)urea

1-[(4-Butylphenyl)methyl]-1-(6-cyanohexyl)-3-(2,4,6-trichlorophenyl)urea

1-[(4-Butylphenyl)methyl]-1-(6-chlorohexyl)-3-(2,4,6-trichlorophenyl)urea

1-(4-Phenylbenzyl)-1-(3,4-dichlorobenzyl)-3-(2,4-dimethylphenyl)urea

1-(3,4-Dimethylbenzyl)-1-(2-chlorobenzyl)-3-(2,4-dimethylphenyl)urea

1-(3,3-Dimethylbutyl)-1-[4-(n-butyl)benzyl]-3-(4-chloro-2-methylphenyl)urea

1-(3,3-Dimethylbutyl)-1-[4-(n-butoxy)benzyl]-3-(4-chloro-2-methylphenyl)urea

1-(3,3-Dimethylbutyl)-1-[4-(n-butoxy)benzyl]-3-(2,4,6-trichlorophenyl)urea

1-(3,3-Dimethylbutyl)-1-[4-(n-butoxy)benzyl]-3-(2,4-difluorophenyl)urea

1-(3,3-Dimethylbutyl)-1-[4-(n-butyl)benzyl]-3-(2,4-difluorophenyl)urea

1-(3,3-Dimethylbutyl)-1-[4-(n-butyl)benzyl]-3-(2,4,6-trichlorophenyl)urea

1-(5,5-Dimethylhexyl)-1-[4-(n-butyl)benzyl]-3-(4-chloro-2-methylphenyl)urea

1-(3,3-Dimethylbutyl)-1[4-(2,2-dimethylpropyl)benzyl]-3-(2,4-difluorophenyl)urea

1(3,3-Dimethylbutyl)-1-[4-(2,2-dimethylpropyl)benzyl]-3-(4-chloro-2-methylphenyl)urea

1-(3,3-Dimethylbutyl)-1-[4-(2,2-dimethylpropyl)benzyl]-3-(2,4,6-trichlorophenyl)urea

1-(3,3-Dimethylbutyl)-1-[4-(n-butyl)benzyl]-3-(4-chloro-2,6-dimethylphenyl)urea

1-(3,3-Dimethylbutyl)-1-(4-chlorobenzyl)-3-(4-chloro-2,6-dimethylphenyl)urea

1-(n-Heptyl)-1-[4-(n-butyl)benzyl]-3-(4-chloro-2,6-dimethylphenyl)urea

1-(3,3-Dimethylbutyl)-1-[4-(2,2-dimethylpropyl)benzyl]-3-(4-chloro-2,6-dimethylphenyl)urea

1-(n-Heptyl)-1-[4-(n-butyl)benzyl]-3-(4-chloro-2,5-dimethylphenyl)urea

1-(3,3-Dimethylbutyl)-1-(benzyl)-3-(4-chloro-2,5-dimethylphenyl)urea

1-(n-Heptyl)-1-[4-(2,2-dimethylpropyl)phenylmethyl]-3-(2,4-difluorophenyl)urea

1-(n-Heptyl)-1-[4-(2,2-dimethylpropyl)phenylmethyl]-3-(4-chloro-2,6-dimethylphenyl)urea

1-(n-Heptyl)-1-[4-(2,2-dimethylpropyl)phenylmethyl]-3-(2,4,6-trifluorophenyl)urea

This invention also relates to a method of treating atherosclerosis inmammals which comprises administering to said mammal an effective amountof a compound as recited above.

This invention also relates to a method of reducing the cholesterolcontent of the arterial walls of mammals which comprises administeringto said mammal an effective amount of a compound as recited above.

This invention also relates to a method of treating hyperlipidemia inmammals which comprises administering to said mammal an effective amountof a compound as recited above.

This invention further relates to a method of inhibiting atheroscleroticlesion development in mammals which comprises administering to saidmammal an effective amount of a compound as recited above.

This invention still further relates to pharmaceutical compositionswhich comprise an effective antiatherosclerotic amount of a compound asrecited above in association with a pharmaceutically acceptable carrier.

Finally, this invention relates to processes for preparing compounds asrecited above. One process especially useful for the preparation ofureas and thioureas of Formula I involves reacting an arylisocyanate orarylisothiocyanate of Formula III with a secondary amine of Formula IV,wherein X, Y, R₁, and R₂ are as defined above. ##STR5##

A second process for the preparation of ureas and thioureas of Formula Iinvolves reacting a compound of Formula V; wherein E and B are leavinggroups, which may be the same or different, selected from the groupconsisting of halo, (C₁ -C₄)alkoxy, (C₁ -C₄)alkylthio, phenoxy,4-chlorophenoxy, and 4-nitrophenoxy; with a secondary amine of FormulaIV to yield an intermediate of Formula VI and then reacting theintermediate with an arylamine of Formula VII, wherein X, Y, R₁, and R₂are as defined above. ##STR6##

A third process for the preparation of ureas and thioureas of Formula Iinvolves reacting a compound of Formula V with an arylamine of FormulaVII to yield an intermediate of Formula VIII, wherein X, Y, E, and B areas defined above, and then reacting this intermediate with a secondaryamine of Formula IV. ##STR7##

DETAILED DESCRIPTION OF THE INVENTION

Many of the novel ureas and thioureas of this invention are prepared byreacting arylisocyanates and arylisothiocyanates with secondary amines.These reactions may be performed in aprotic solvents such as hexane,diethyl ether, toluene, tetrahydrofuran, and the like at temperaturesfrom room temperature or below up to the boiling point of the solventused. The ureas and thioureas are isolated by filtration or byevaporation of the solvent, and they may be purified byrecrystallization, absorption chromatography, or distillation underreduced pressure. Examples of this process are the reaction of2,4-dimethylphenylisocyanate with N-benzyl-N-(n-butyl)amine to yield1-benzyl-1-(n-butyl)-3-(2,4-dimethylphenyl)urea and the reaction of6-[[(4-butylphenyl)methyl]amino]-1-hexanol with 2,4-dimethylphenylisocyanate in hexane at room temperature to yield1-[(4-butylphenyl)methyl]-3-(2,4-dimethylphenyl)-1-(6-hydroxyhexyl)urea.

Many of the secondary amines required for the synthesis of the ureas andthioureas of this invention are prepared by reductions of thecorresponding amides. Reagents used for these reductions includeddiborane, lithium aluminum hydride, and sodiumdihydrobis(2-methoxyethoxy)aluminate. Examples of this reaction are thesyntheses of: 6-[[(4-butylphenyl)methyl]amino]--hexanol from4-butyl-N-(6-hydroxyhexyl)benzamide by treatment with 1Mborane-tetrahydrofuran complex in tetrahydrofuran;4-butyl-N-[5-(trimethylsilyl)pentyl]benzenemethanamine fromN-[(4-butylphenyl)methyl]-5-(trimethylsilyl)pentanamide by treatmentwith lithium aluminum hydride in tetrahydrofuran;3,3-dimethylbutyl-2-thiophenemethanamine from3,3-dimethylbutyl-2-thiophenecarboxamide by treatment with Vitride® T[sodium dihydrobis(2-methoxyethoxy)aluminate (70% solution in toluene)];and N-(n-butyl)-2-chlorobenzylamine by diborane reduction ofN-(n-butyl)-2-chlorobenzamide.

Certain of the amides required by these reductions are prepared byacylation of primary amines with carboxylic acids by methods well knownto those skilled in the art, for example, by conversion of thecarboxylic acid to the corresponding carboxylic acid chloride usingthionyl chloride and then reacting the acid chloride with the primaryamine in the presence of a base. One method especially useful for thistransformation is the boron trifluoride etherate catalyzed reaction of acarboxylic acid with a primary amine. An example of this transformationis the boron trifluoride etherate catalyzed acylation of2-chlorobenzylamine with 3-methoxyphenylacetic acid to yieldN-(2-chlorobenzyl)-3-methoxyphenylacetamide. Another example of thisreaction is the preparation of 4-butyl-N-(6-hydroxyhexyl)benzamide from6-amino-1-hexanol, triethylamine and p-butylbenzoyl chloride indichloromethane.

Certain of the novel ureas and thioureas of this invention are preparedby reacting arylamines with activated derivatives of carbonic acid suchas phosgene or thiophosgene to yield an intermediate, for instance, anarylcarbamyl chloride. This intermediate is then reacted with asecondary amine to yield the urea or thiourea. The preparation of thisintermediate is conducted in an aprotic solvent such as tetrahydrofuran,toluene, or xylene at temperatures from about room temperature up to theboiling point of the solvent in the presence of a base, for example,N,N-dimethylaniline. The intermediate is then reacted with an arylaminein an aprotic solvent such as dimethylacetamide in the presence of abase such as sodium hydride at temperatures from about room temperatureup to the boiling point of the solvent used.

Other of the novel ureas and thioureas of this invention are prepared byreacting arylamines with activated derivatives of carbonic acid such asphosgene or thiophosgene to yield an intermediate, for instance, anarylcarbamyl chloride. This intermediate is then reacted with asecondary amine to yield the urea or thiourea. The preparation of thisintermediate is conducted in an aprotic solvent such as toluene orxylene at temperatures from about room temperature up to the boilingpoint of the solvent in the presence of a base, for example,N,N-dimethylaniline.

The intermediate is then reacted with a secondary amine in an aproticsolvent such as toluene at temperatures from room temperature or belowup to the boiling point of the solvent. An example of this process isthe reaction of 2,4-difluoroaniline with phenyl chloroformate to yieldthe intermediate phenyl N-(2,4-difluorophenyl)carbamate which is thenreacted with N-(4-butylphenyl)-N-(6-hydroxyhexyl)amine to yield1-(4-n-butylphenyl)-3-(2,4-difluorophenyl)-1-(6-hydroxyhexyl)urea.

The ureas and thioureas of this invention which contain carboxy groupsare prepared by alkaline hydrolysis of the corresponding carboalkoxyureas and thioureas, prepared by the synthetic methods described above.Likewise, those which contain hydroxy, mercapto, or amino groups areprepared by alkaline hydrolysis of the corresponding O-acetyl, S-acetyl,and N-acetyl ureas and thioureas, respectively, the latter also havingbeen obtained by the urea and thiourea syntheses described above.Alternatively, ureas and thioureas containing hydroxy groups areprepared by cleavage of the corresponding methoxy compounds using Lewisacids such as boron tribromide.

One of the intermediates, 5-(trimethylsilyl)pentanoic acid, was preparedby reaction of the Grignard reagent derived frombromomethyltrimethylsilane with the magnesium salt of 4-bromobutyricacid.

The ureas and thioureas of the present invention, in general, areobtained as crystalline solids or distillable liquids. They arecharacterized by distinct melting and boiling points and unique spectra.They are appreciably soluble in organic solvents but generally lesssoluble in water. Those compounds which contain carboxylic acid groupsmay be converted to their alkali metal and alkaline earth salts bytreatment with the appropriate metal hydroxides, and those which containamino groups may be converted to their ammonium salts by treatment withorganic or mineral acids. Both of these types of salts exhibit increasedwater solubility.

The preparation and properties of the compounds of this invention willbe described in greater detail in conjunction with the specific examplesshown below.

The compounds of the present invention were assayed for two types ofbiological activity related to their potential use asantiatherosclerotic agents. Compounds were tested in vitro for theability to inhibit the enzyme fatty acyl CoA: cholesterol acyltransferase (ACAT) and in vivo for serum hypolipidemic activity asmeausred by the ability to inhibit lipid absorption in rats.

The compounds were tested for their ability to inhibit ACAT according tothe following procedure: rat adrenals were homogenized in 0.2M monobasicpotassium phosphate buffer, pH 7.4, and centrifuged at 1,000 timesgravity for 15 minutes at 5° C. The supernatant, containing themicrosomal fraction, served as the source of the cholesterol-esterifyingenzyme, fatty acyl CoA:cholesterol acyl transferase (ACAT). A mixturecomprising 50 parts of adrenal supernatant, 10 parts of bovine serumalbumin (50 mg/ml), 3 parts of test compound (final concentration 5.2μg/ml), and 500 parts of buffer was preincubated at 37° C. for 10minutes. After treatment with 20 parts of oleoyl CoA (¹⁴ C-0.4 μCi), themixture was incubated at 37° C. for 10 minutes. A control mixture,omitting the test compound, was prepared and treated in the same manner.The lipids from the incubation mixture was extracted into an organicsolvent and separated by thin-layer chromatography. The cholesterylester fraction was counted in a scintillation counter. This procedure isa modification of that described by Hashimoto, et al., Life Scie., 12(Part II), 1-12 (1973).

Compounds which produced statistically significant inhibition of theACAT enzyme are considered to be active. The results of this test onrepresentative compounds of this invention appear in Table I.

                  TABLE 1    ______________________________________    Compound                 % Inhibition    ______________________________________    1-Benzyl-1-( -n-butyl)-3-(3-methylphenyl)-                             92.3    urea    1-Benzyl-1-( -n-butyl)-3-(3-trifluoromethyl-                             85.7    phenyl)urea    1-Benzyl-1-( -n-butyl)-3-(3,5-dichlorophen-                             90.7    yl)urea    1-Benzyl-1-( -n-butyl)-3-(3,4-dichlorophen-                             95.9    yl)urea    1-Benzyl-1-( -n-butyl)-3-(3-chlorophenyl)-                             88.6    urea    1-Benzyl-1-( -n-butyl)-3-(2,4-dimethylphen-                             91.3    yl)urea    1-Benzyl-1-( -n-butyl)-3-(2-methylphenyl)-                             78.8    urea    1-Benzyl-1 ( -n-butyl)-3-(4-methylphenyl)-                             78.0    urea    1-Benzyl-1-( -n-butyl)-3-(2,3-dimethylphen-                             85.8    yl)urea    1-Benzyl-1-( -n-butyl)-3-(2,5-dimethylphen-                             92.7    yl)urea    1-Benzyl-1-( -n-butyl)-3-(2,6-dimethylphen-                             83.1    yl)urea    1-Benzyl-1-( -n-butyl)-3-(3,5-dimethylphen-                             94.2    yl)urea    1-Benzyl-1-[1-(3-methoxyphenyl)-2-phenyl-                             86.4    ethyl]-3-(2,4-dimethylphenyl)urea    1-Benzyl-1-[1-(4-benzyloxyphenyl)-2-phen-                             93.0    ylethyl]-3-(2,4-dimethylphenyl)urea    1-Benzyl-1-(1,2-diphenylethyl)-3-(2,4-di-                             95.0    methylphenyl)urea    1-Benzyl-1-( -n-butyl)-3-(3,4-dimethylphen-                             87.1    yl)urea    1-Benzyl-1-[1-(3-methoxyphenyl)-2-phenyl-                             88.1    ethyl]-3-(3-trifluoromethylphenyl)urea    1-Benzyl-1-( -n-butyl)-3-(3-chloro-2-methoxy-                             84.5    phenyl)urea    1-Benzyl-1-( -n-butyl)-3-(5-chloro-2-methoxy-                             80.6    phenyl)urea    1-Benzyl-1-(n-butyl)-3-phenyl thiourea                             82.4    1-(n-Butyl)-1-(2-fluorobenzyl)-3-(2,4-di-                             83.6    methylphenyl)urea    1-(n-Butyl)-1-(4-fluorobenzyl)-3-(2,4-di-                             80.6    methylphenyl)urea    1-(n-Butyl)-1-(2-chlorobenzyl)-3-(2,4-di-                             95.5    methylphenyl)urea    1-(n-Butyl)-1-(2,6-dichlorobenzyl)-3-(2,4-                             74.5    dimethylphenyl)urea    1-(n-Butyl)-1-(4-bromobenzyl)-3-(2,4-di-                             81.0    methylphenyl)urea    1-(n-Butyl)-1-[4-(n-butyl)benzyl)-3-(2,4-                             94.4    dimethylphenyl)urea    1-(n-Butyl)-1-(4-methylbenzyl)-3-(2,4-di-                             96.7    methylphenyl)urea    1-(n-Butyl)-1-(4-tert-butylbenzyl)-3-(2,4-                             96.4    dimethylphenyl)urea    1-(n-Butyl)-1-(4-chlorobenzyl)-3-(2,4-di-                             94.6    methylphenyl)urea    1-(n-Butyl)-1-(4-methoxybenzyl)-3-(2,4-di-                             94.2    methylphenyl)urea    1-(n-Butyl)-1-(3,4-methylenedioxybenzyl)-                             88.2    3-(2,4-dimethylphenyl)urea    1-(n-Butyl)-1-(4-trifluoromethylbenzyl)-3-                             93.3    (2,4-dimethylphenyl)urea    1-(n-Butyl)-1-(4-phenylbenzyl)-3-(2,4-di-                             97.1    methylphenyl)urea    1-(n-Decyl)-1-benzyl-3-(2,4-dimethyl-                             96.1    phenyl)urea    1-(n-Butyl)-1-(2-phenylethyl)-3-(2,4-di-                             87.9    methylphenyl)urea    1-(n-Butyl)-1-[2-(4-fluorophenyl)ethyl]-                             96.1    3-(2,4-dimethylphenyl)urea    1-(n-Butyl)-1-[2-(4-chlorophenyl)ethyl]-                             93.3    3-(2,4-dimethylphenyl)urea    1-(n-Butyl)-1-[2-(3-methoxyphenyl)ethy]-                             98.3    3-(2,4-dimethylphenyl)urea    1-(n-Butyl)-1-(3-phenylpropyl)-3-(2,4-di-                             97.4    methylphenyl)urea    1-(n-Butyl)-1-benzyl-3-(2,4,6-trimethyl-                             75.8    phenyl)urea    1-(n-Butyl)-1-[4-(n-hexyl)benzyl]-3-(2,4-                             93.8    dimethylphenyl)urea    1-(n-Tetradecyl)-1-benzyl-3-(2,4-dimethyl-                             80.3    phenyl)urea    1-(n-Butyl)-1-[2-(3-bromophenyl)ethyl]-3-                             97.0    (2,4-dimethylphenyl)urea    1-[2-(3,4-Dimethoxyphenyl)ethyl]-1-                             53.3    (3-chloro-4-methylbenzyl)-3-(2,4-    dimethylphenyl)urea    1-[2-(2-Methylphenyl)ethyl]-1-(4-bromo-                             29.2    benzyl)-3-(2,4-dimethylphenyl)urea    1-[2-(3-Trifluoromethylphenyl)ethyl]-1-                             7.8    (2-chlorobenzyl)-3-(2,4-dimethylphenyl)    urea    1-(2-Fluorobenzyl)-1-(2-methoxybenzyl)-                             41.5    3-(2,4-dimethylphenyl)urea    1-[2-(3,4-Dimethoxyphenyl)ethyl]-1-                             57.4    (4-fluorobenzyl)-3-(2,4-dimethyl-    phenyl)urea    1-[2-(4-Ethoxyphenyl)ethyl]-1-(2,4-di-                             34.9    methylbenzyl)-3-(2,4-dimethylphenyl)urea    1-[2-(3-Methylphenyl)ethyl]-1-(3-nitro-                             95.7    benzyl)-3-(2,4-dimethylphenyl)urea    1-[2-(2,5-Dimethoxyphenyl)ethyl]-1-(3-                             97.1    chlorobenzyl)-3-(2,4-dimethylphenyl)urea    1-(n-Butyl)-1-(2-methyl-2,2-diphenyl)                             97.4    ethyl-3-(2,4-dimethylphenyl)urea    1-(n-Butyl)-1-(4-hexyloxybenzyl)-3-                             97.1    (2,4,6-trimethylphenyl)urea    1-(n-Butyl)-1-(4-heptyloxybenzyl)-3-                             97.3    (2,4,6-trimethylphenyl)urea    1-(n-Butyl)-1-benzyl-3-(4-trifluoro-                             87.8    acetylamino-3,5-dichlorophenyl)urea    1-Benzyl-1-(4-n-butylbenzyl)-3-(2,4-                             91.9    dimethylphenyl)urea    1-Benzyl-1-(4-n-butylbenzyl)-3-(2,4,6-                             92.8    trimethylphenyl)urea    1-Benzyl-1-(4-n-butylbenzyl)-3-(4-n-                             92.0    butylphenyl)urea    1-Benzyl-1-(4-n-butylbenzyl)-3-(4-                             93.5    phenoxyphenyl)urea    1-(n-Heptyl)-1-(4-n-butylbenzyl)-3-                             94.8    (2,4-dimethylphenyl)urea    1-(n-Heptyl)-1-(4-n-butylbenzyl)-3-                             95.3    (2,4,5-trimethylphenyl)urea    1-Benzyl-1- [2-phenyl-1-(4-benzyloxy-                             93.7    phenyl)ethyl]-3-(2,4,5-trimethylphenyl)urea    1-(n-Heptyl)-1-(4-butyloxybenzyl)-3-                             94.6    (2,4-dimethylphenyl)urea    1-(n-Heptyl)-1-(4-butyloxybenzyl)-3-                             95.6    (2,4,5-trimethylphenyl)urea    1-Benzyl-1-(4-butyloxybenzyl)-3-(2,4-                             91.7    dimethylphenyl)urea    1-Benzyl-1-(4-butyloxybenzyl)-3-(2,4,5-                             95.8    trimethylphenyl)urea    1-Benzyl-1-(4-n-butylbenzyl)-3-(2,4,5-                             90.5    trimethylphenyl)urea    1-Benzyl-1[2-phenyl-1-(4-benzyloxyphenyl                             90.0    ethyl]-3-(2,4,6-trimethylphenyl)urea    1-(n-Heptyl)-1-(4-n-butoxybenzyl)-3-                             90.0    (2,4,6-trichlorophenyl)urea    1-(n-Heptyl)-(4-n-butoxybenzyl)-3-(2,4-                             79.9    dichlorophenyl)urea    1-(n-Heptyl)-(4-n-butoxybenzyl)-3-(2-                             89.4    trifluoromethyl-4-chlorophenyl)urea    1-Benzyl-1-(4-n-butoxybenzyl)-3-(2,4,6-                             95.2    trichlorophenyl)urea    1-Benzyl-1-(4-n-butoxybenzyl)-3-(2,4-                             80.0    dichlorophenyl)urea    1-Benzyl-1-(4-n-butoxybenzyl)-3-(2-                             85.0    trifluoromethyl-4-chlorophenyl)urea    1-(n-Heptyl)-1-(4-n-butoxybenzyl)-3-(3-                             82.4    trifluoromethylphenyl)urea    1-(n-Benzyl-1-(4-n-butoxybenzyl)-3-(3-                             87.0    trifluoromethylphenyl)urea    1-(n-Heptyl)-1-(4-n-butylbenzyl)-3-(2,4-                             80.0    dichlorophenyl)urea    1-(n-Heptyl)-1-(4-n-butylbenzyl)-3-(2-                             90.0    trifluoromethyl-4-chlorophenyl)urea.    1-(n-Heptyl)-1-(4-n-butylbenzyl)-3-                             90.0    (2,4,6-trichlorophenyl)urea    1-(n-Heptyl)-1-(4-n-butylbenzyl)-3-                             85.0    (3-trifluoromethylphenyl)urea    1-(n-Heptyl)-1-(4-n-butylbenzyl)-3-                             46.5    (2,4,5-trichlorophenyl)urea    1-Benzyl-1-(4-n-butylbenzyl)-3-(2-                             94.3    methyl-4-chlorophenyl)urea    1-(n-Heptyl)-1-(4-n-butoxybenzyl)-3-                             82.7    (2,4-difluorophenyl)urea    1-(n-Heptyl)-1-(4-n-butoxybenzyl)-3-(2-                             91.7    methyl-4-chlorophenyl)urea    1-(n-Heptyl)-1-(2-furyl)-3-(2,4,5-tri-                             93.8    methylphenyl)urea    1-(n-Heptyl)-1-(2-furyl)-3-(2,4,6-tri-                             96.1    chlorophenyl)urea    1-(n-Heptyl)-1-(4-n-butylbenzyl)-3-(2-                             92.5    methyl-4-chlorophenyl)urea    1-(n-Heptyl)-1-(4-n-butylbenzyl)-3-(2,4-                             90.0    difluorophenyl)urea    1-(n-Heptyl)-1-(4-n-butylbenzyl)-3-(4-                             92.4    carboethoxyphenyl)urea    1-(n-Heptyl)-1-(4-n-butylbenzyl)-3-(2-                             97.4    methylphenyl)urea    1-(n-Heptyl)-1-(4-n-butylbenzyl)-3-(3-                             93.8    methylphenyl)urea    1-(n-Heptyl)-1-(4-n-butylbenzyl)-3-(4-                             61.8    carboxyphenyl)urea    1-(n-Heptyl)-1-(2-phenylethyl)-3-(2-                             93.8    methyl-4-chlorophenyl)urea    1-(n-Heptyl)-1-(2-phenylethyl)-3-(2,4,5-                             77.3    trichlorophenyl)urea    1-(n-Heptyl)-1-(2-phenylethyl)-3-(2-                             88.3    trifluoromethyl-4-chlorophenyl)urea    1-(n-Heptyl)-1-(2-phenylethyl)-3-(2,4-                             95.7    dimethylphenyl)urea    1-(n-Heptyl)-1-(2-phenylethyl)-3-(2,4-                             91.8    dichlorophenyl)urea    1-(n-Heptyl)-1-(2-phenylethyl)-3-(2,4-                             94.1    difluorophenyl)urea    1-(n-Heptyl)-1-(2-phenylethyl)-3-(3-                             88.4    trifluoromethylphenyl)urea    1-Benzyl-1-[2-phenyl-1-(4-benzyloxyphen-                             95.0    yl)ethyl]-3-(2,4,6-trichlorophenyl)urea    1-(4-n-Pentylbenzyl)-1-(4-n-pentyloxy-                             95.5    benzyl)-3-(2,4,6-trichlorophenyl)urea    1-(4-n-Pentylbenzyl)-1-(4-n-pentyloxy-                             85.0    benzyl)-3-(2,4 dichlorophenyl)urea    1-(4-n-Pentylbenzyl)-1-(4-n-pentyloxy-                             80.0    benzyl)-3-(2,4,5-trichlorophenyl)urea    1-(4-n-Pentylbenzyl)-1-(4-n-pentyloxy-                             81.0    benzyl)-3-(2-trifluoromethyl-4-chloro-    phenyl)urea    1-(4-n-Pentylbenzyl)-1-(4-n-pentyloxy-                             85.0    benzyl)-3-(3-trifluoromethylphenyl)urea    1-(4-n-Pentylbenzyl)-1-(4-n-pentyloxy-                             90.0    benzyl)-3-(2,4-difluorophenyl)urea    1-(4-n-Pentylbenzyl)-1-(4-n-pentyloxy-                             91.0    benzyl)-3-(2-methyl-4-chlorophenyl)urea    1-(4-Chlorobenzyl)-1-(1-naphthylmethyl)-                             77.0    3-(2,4,6-trichlorophenyl)urea    1-(4-Chlorobenzyl)-1-(1-naphthylmethyl)-                             94.0    3-(2-methyl-4-chlorophenyl)urea    1-(4-Chlorobenzyl)-1-(1-naphthylmethyl)-                             84.0    3-(2,4-difluorophenyl)urea    1-(4-Chlorobenzyl)-1-(1-naphthylmethyl)-                             80.0    3-(3-trifluoromethylphenyl)urea    1-(4-Chlorobenzyl)-1-(1-naphthylmethyl)-                             86.0    3-(2,4,5-trichlorophenyl)urea    1-Benzyl-1-[2-phenyl-1-(4-benzyloxyphen-                             95.0    yl)ethyl]-3-(2,4,5-trichlorophenyl)urea    1-Benzyl-1-(4-n-butyloxybenzyl)-3-(2,4,5-                             89.0    trichlorophenyl)urea    1-Benzyl-1-[2-phenyl-1-(4-benzyloxyphen-                             70.0    yl)ethyl]-3-(2,4-difluorophenyl)urea    1-Benzyl-1-(4-n-butoxybenzyl)-3-(2,4-                             88.0    difluorophenyl)urea    1-Benzyl-1-[2-phenyl-1-(4-benzyloxyphe-                             91.0    nyl)ethyl]-3-(2,4-difluorophenyl)urea    1-Benzyl-1-[2-phenyl-1-(4-benzyloxyphe-                             92.0    nyl)ethyl]-3-(2-trifuoromethyl-4-    chlorophenyl)urea    1-Benzyl-1-[2-phenyl-1-(4-benzyloxyphe-                             74.0    nyl)ethyl]-3-(3-trifluoromethylphenyl)urea    1-[(4-Butylphenyl)methyl]-3-(2,4-dimethyl-                             96.8    phenyl)-1-(6-hydroxyhexyl)urea    1-[(4-Butylphenyl)methyl]-1-(6-hydroxy-                             90.0    hexyl)-3-(2,4,5-trimethylphenyl)urea    1-[(4-Butylphenyl)methyl]-1-[2-(2-hydroxy-                             85.9    ethoxy)ethyl]-3-(2,4,5-trimethylphenyl)urea    1-[(4-Butylphenyl)methyl]-3-(2,4-dimethyl-                             74.5    phenyl)-1-[2-(2-hydroxyethoxy)ethyl]urea    1-(2-Furanylmethyl)-1-heptyl-3-(2,4,5-                             93.8    trimethylphenyl)urea    1-(2-Furanylmethyl)-1-heptyl-3-(2,4,6-                             96.1    trichlorophenyl)urea    1-Heptyl-1-(2-thienylmethyl)-3-(2,4,5-                             90.0    trimethylphenyl)urea    1-Heptyl-1-(2-thienylmethyl)-3-(2,4,6-                             90.0    trichlorophenyl)urea    1-[(4-Butoxyphenyl)methyl]-1-(2-thienyl-                             90.0    methyl)-3-(2,4,5-trimethylphenyl)urea    1-[(4-Butylphenyl)methyl]-1-[6-[(methyl-                             90.0    sulfonyl)oxy]hexyl]-3-[(2,4,5-trimethyl-    phenyl)methyl]urea    1-[(4-Butylphenyl)methyl]-1-(6-cyanohexyl)-                             90.0    3-(2,4,5-trimethylphenyl)urea    1-[(4-Butylphenyl)methyl]-1-(6-chlorohex-                             90.0    yl)-3-(2,4,5-trimethylphenyl)urea    1-[(4-Butylphenyl)methyl]-3-(4-chloro-2-                             90.0    methylphenyl)-1-(6-hydroxyhexyl)urea    1-[(4-Butylphenyl)methyl]-3-(4-chloro-2-                             90.0    methylphenyl)-1-[6-[(methylsulfonyl)oxy]-    hexyl]urea    1-[(4-Butylphenyl)methyl]-3-(4-chloro-2-                             90.0    methylphenyl)-1-(6-cyanohexyl)urea    1-[(4-Butylphenyl)methyl]-1-(6-chlorohex-                             90.0    yl)-3-(4-chloro-2-methylphenyl)urea    1-[(4-Butylphenyl)methyl]-1-(6-hydroxy-                             90.0    hexyl)-3-(2,4,6-trichlorophenyl)urea    1-[(4-Butylphenyl)methyl]-1-[6-(methyl-                             90.0    sulfonyloxy)hexyl]-3-(2,4,6-trichloro-    phenyl)urea    1-[(4-Butylphenyl)methyl]-1-(6-cyanohex-                             90.0    yl)-3-(2,4,6-trichlorophenyl)urea    1-[(4-Butylphenyl)methyl]-1-(6-chlorohex-                             90.0    yl)-3-(2,4,6-trichlorophenyl)urea    1-[(4-Butylphenyl)methyl]-3-(4-chloro-2-                             90.0    methylphenyl)-1-[5-(trimethylsilyl)pentyl]urea    1-[(4-Butylphenyl)methyl]-3-(2,4-difluoro-                             90.0    phenyl)-1-[5-(trimethylsilyl)pentyl]urea    3-(2,4-Difluorophenyl)-1-(3,3-dimethyl-                             90.0    butyl)-1-(2-thienylmethyl)urea    3-(4-Chloro-2-methylphenyl)-1-(3,3-di-                             90.0    methylbutyl)-1-(2-thienylmethyl)urea    1-(3,3-Dimethylbutyl)-1-(2-thienylmethyl)-                             90.0    3-(2,4,6-trichlorophenyl)urea    1-Benzyl-1-[2-phenyl-1-(4-benzyloxyphe-                             89.3    nyl)ethyl]-3-(2-methyl-4-chlorophenyl)urea    1-(4-Chlorobenzyl)-1-(1-naphthylmethyl)-                             92.0    3-(2,4-dichlorophenyl)urea    1-(4-Chlorobenzyl)-1-(1-naphthylmethyl)-                             83.0    3-(2-trifluoromethyl-4-choropnenyl)urea    1-[2-(4-Methylphenyl)ethyl]-1-(3-chloro-                             67.6    benzyl)-3-(2,4-dimethylphenyl)urea    1-[2-(4-Ethoxyphenyl)ethyl]-1-(2-chloro-                             94.1    benzyl)-3-(2,4-dimethylphenyl)urea    1-(4-Phenylbenzyl)-1-(3,4-dichlorobenzyl)-                             36.3    3-(2,4-dimethylphenyl)urea    1-(n-Butyl)-1-benzyl-3-(3-chloro-2-hydroxy-                             71.0    phenyl)urea    1-[2-(3-Fluorophenyl)ethyl]-1-(4-methyl-                             80.5    benzyl)-3-(2,4-dimethylphenyl)urea    1-(n-Butyl)-1-benzyl-3-(2-nitrophenyl)-                             37.0    urea    1-(3,4-Methylenedioxyphenyl)-1-(3,3-di-                             87.8    phenylpropyl)-3-(2,4-dimethylphenyl)urea    1-(n-Butyl)-1-[3-(3,4-dimethoxyphenyl)-                             36.4    propyl]-3-(2,4-dimethylphenyl)urea    1-(3,4-Dimethylbenzyl)-1-(2-chlorobenzyl)-                             92.9    3-(2,4-dimethylphenyl)urea    1-(n-Butyl)-1-benzyl-3-(2,4,6-trichloro-                             87.8    phenyl)urea    1-(n-Butyl)-1-benzyl-3-(2-hydroxy-5-                             85.6    chlorophenyl)urea    1-(3,4-Methylenedioxybenzyl)-1-[2-(4-                             41.2    methylphenyl)ethyl]-3-(2,4-dimethyl-    phenyl)urea    1-(n-Butyl)-1-benzyl-3-(4-amino-3,5-                             61.1    dichlorophenyl)urea    1-(n-Butyl)-1-(benzyl)-3-[4-(chloroacet-                             72.9    amido)-3,5-dichlorophenyl]urea    1-[2-(2-Chlorophenyl)ethyl]-1-(3,4-di-                             92.8    methylbenzyl)-3-(2,4-dimethylphenyl)urea    1-[2-(2-Chlorophenyl)ethyl]-1-(3-methyl-                             56.1    benzyl)-3-(2,4-dimethylphenyl)urea    1-(n-Butyl)-1-benzyl-3-(4-chloro-2-                             89.0    methylphenyl)urea    1-(3,3-Dimethylbutyl)-1-[4-(n-butyl)-                             90.5    benzyl]-3-(4-chloro-2-methylphenyl)urea    1-(3,3-Dimethylbutyl)-1-[4-(n-butoxy)-                             90.0    benzyl]-3-(4-chloro-2-methylphenyl)urea    1-(3,3-Dimethylbutyl)-1-[4-(n-butoxy)-                             90.0    benzyl]-3-(2,4,6-trichlorophenyl)urea    1-(3,3-Dimethylbutyl)-1-[4-(n-butoxy)-                             90.0    benzyl]-3-(2,4-difluorophenyl)urea    1-(3,3-Dimethylbutyl)-1-[4-(n-butyl)-                             90.0    benzyl]-3-(2,4-difluorophenyl)urea    1-(3,3-Dimethylbutyl)-1-[4-(n-butyl)-                             90.0    benzyl]-3-(2,4,6-trichlorophenyl)urea    1-(5,5-Dimethylhexyl)-1-[4-(n-butyl)ben-                             90.0    zyl]-3-(4-chloro-2-methylphenyl)urea    1-(5,5-Dimethylhexyl)-1-[4-(n-butyl)ben-                             90.0    zyl]-3-(2,4-difluorophenyl)urea    1-(5,5-Dimethylhexyl-1-[ 90.0n-butyl)ben-    zyl]-3-(2,4,6-trichlorophenyl)urea    1-(3,3-Dimethylbutyl)-1-(4-chlorobenzyl)-                             90.0    3-(4-chloro-2-methylphenyl)urea    1-(3,3-Dimethylbutyl)-1-benzyl-3-(2,4-                             90.0    dif1uorophenyl)urea    1-(3,3-Dimethylbutyl)-1-(4-chlorobenzyl)-                             90.0    3-(2,4-difluorophenyl)urea    1-(3,3-Dimethylbutyl)-1-(4-chlorobenzyl)-                             90.0    3-(2,4,6-trichlorophenyl)urea    1-(n-Heptyl)-1-[4-(n-butyl)benzyl]-3-(3-                             90.0    trifluoromethylphenyl)urea    1-(3,3-Dimethylbutyl)-1-[4-(n-butyl)ben-                             90.0    zyl]-3-(3-trifluoromethylphenyl)urea    1-(3,3-Dimethylbutyl)-1-(4-chlorobenzyl)-                             90.0    3-(3-trifluoromethylphenyl)urea    1-(3,3-Dimethylbutyl)-1-[4-(2,2-dimethyl-                             90.0    propyl)benzyl]-3-(2,4-difluorophenyl)urea    1-(3,3-Dimethylbutyl)-1-[4-(2,2-dimethyl-                             90.0    propyl)benzyl]-3-(4-chloro-2-methylphenyl)    urea    1-(3,3-Dimethylbutyl)-1-[4-(2,2-dimethyl-                             90.0    propyl)benzyl]-3-(2,4,6-trichlorophenyl)    urea    1-(3,3-Dimethylbutyl)-1-[4-(n-butyl)ben-                             90.0    zyl]-3-(4-chloro-2,6-dimethylphenyl)urea    1-(3,3-Dimethylbutyl)-1-(4-chlorobenzyl)-                             90.0    3-(4-chloro-2,6-dimethylphenyl)urea    1-(n-Heptyl)-1-[4-(n-butyl)benzyl]-3-(4-                             90.0    chloro-2,6-dimethylphenyl)urea    1-(3,3-Dimethylbutyl)-1-[4-(2,2-dimethyl-                             90.0    propyl)benzyl]-3-(4-chloro-2,6-dimethyl-    phenyl)urea    1-(3,3-Dimethylbutyl)-1-benzyl-3-(4-                             90.0    chloro-2-methylphenyl)urea    1-(n-Heptyl)-1-[4-(n-butyl)benzyl]-3-(4-                             90.0    chloro-2,5-dimethylphenyl)urea    1-(3,3-Dimethylbutyl)-1-(benzyl)-3-(4-                             90.0    chloro-2,5-dimethylphenyl)urea    1-( -n-Heptyl)-1-[4-( -n-butyl)benzyl]-3-                             90.0    (2,4,6-trifluorophenyl)urea    1-(3,3-Dimethylbutyl)-1-[4-(n-butyl)ben-                             90.0    zyl]-3-(2,4,6-trifluorophenyl)urea    1-(3,3-Dimethylbutyl)-1-[4-(2,2-dimethyl-                             90.0    propyl)benzyl]-3-(2,4,6-trifluorophenyl)urea    1-(3,3-Dimethylbutyl)-1-benzyl-3-(2,4,6-                             90.0    trifluorophenyl)urea    ______________________________________

In addition to the above described test and the results given in termsof percent inhibition, various compounds of this invention were testedby the same procedure at several concentrations. The results of thistest are given in Table II in terms of IC₅₀ (μM), that concentrationwhich produced 50% inhibition of the ACAT enzyme.

                  TABLE II    ______________________________________    Compound                  IC.sub.50 (μM)    ______________________________________    1-(6-Hydroxyheptyl)-1-[4-(2,2-dimethylpropyl)-                              1.13    benzyl]-3-(4-chloro-2,6-dimethylphenyl)urea    1-(Isopentyl)-1-[4-(isopropyl)benzyl]-3-(2,4-                              3.37    difluorophenyl)urea    1-(Isopentyl)-1-[4-(isopropyl)benzyl]-3-(4-                              0.54    chloro-2,6-dimethylphenyl)urea    1-(Isopentyl)-1-[4-(isopropyl)benzyl]-3-(2,4,6-                              0.53    trifluorophenyl)urea    1-(n-Heptyl)-1-[4-(isobutyl)benzyl]-3-(4-                              1.84    chloro-2-methylphenyl)urea    1-(n-Heptyl)-1-[4-(isopropyl)benzyl]-3-(2,4-                              1.17    difluorophenyl)urea    1-(n-Heptyl)-1-[4-(isopropyl)benzyl]-3-(4-                              0.20    chloro-2,6-dimethylphenyl)urea    1-(n-Heptyl)-1-[4-(isopropyl)benzyl]-3-(4-                              1.74    chloro-2-methylphenyl)urea    1-(n-Heptyl)-1-[4-(isopropyl)benzyl]-3-(2,4,6-                              0.35    trifluorophenyl)urea    1-(n-Heptyl)-1-[4-(4-isopentyl)benzyl]-3-(4-                              2.40    chloro-2-methylphenyl)urea    1-(n-Heptyl)-1-[4-(isopentyl)benzyl]-3-(4-                              0.13    chloro-2,6-dimethylphenyl)urea    1-(n-Heptyl)-1-[4-(4-hydroxybutyl)benzyl]-3-                              0.82    (4-chloro-2,6-dimethylphenyl)urea    1-(n-Heptyl)-1-[4-(3-carboxypropyl)benzyl]-3-                              7.22    (4-chloro-2,6-dimethylphenyl)urea    1-(n-Heptyl)-1-[4-(4-chlorobutyl)benzyl]-3-                              0.11    (4-chloro-2,6-dimethylphenyl)urea    1-(n-Heptyl)-1-[4-(3-carboethoxypropyl)benzyl]-                              1.08    3-(4-chloro-2,6-dimethylphenyl)urea    ______________________________________

The compounds of this invention were tested in vitro at severalconcentrations for their ability to inhibit the enzyme fatty acylCoA:cholesterol acyl transferase (ACAT) using the hereinabove describedprocedure except that the enzyme was derived from microsomes isolatedfrom rat intestinal mucosal cells rather than rat adrenal cells. Theresults of this test on representative compounds of this invention aregiven in Table III in terms of IC₅₀ (μM), that concentration whichproduced 50% inhibition of the ACAT enzyme.

                  TABLE III    ______________________________________    Compound                  IC.sub.50 (μM)    ______________________________________    1-(n-Heptyl)-1-[4-(carbomethoxymethyl)benzyl]-                              1.75    3-(2,4-difluorophenyl)urea    1-(n-Heptyl)-1-[4-(carboxymethyl)benzyl]-3-                              24.0    (2,4-difluorophenyl)urea    1-(n-Heptyl)-1-[4-(3-carboxypropyl)benzyl]-3-                              1.02    (4-chloro-2,6-dimethylphenyl)urea    1-(n-Heptyl)-1-[4-(4-isopropylthiobutyl)ben-                              3.27    zyl]-3-(2,4-difluorophenyl)urea    1-(n-Heptyl)-1-[4-(cyclopentylmethyl)benzyl]-3-                              0.14    (2,4-difluorophenyl)urea    1-(n-Heptyl)-1-[4-(hydroxymethyl)benzyl]-3-                              0.20    (2,4-difluorophenyl)urea    1-(n-Heptyl)-1-[4-(acetoxymethyl)benzyl]-3-                              0.12    (2,4-difluorophenyl)urea    1-(n-Heptyl)-1-[4-(2-isopropylthioethyl)ben-                              0.21    zyl]-3-(2,4-difluorophenyl)urea    1-(n-Heptyl)-1-[4-(2,3-dimethylpentyl)benzyl]-                              0.02    3-(4-chloro-2,6-dimethylphenyl)urea    1-(n-Heptyl)-1-[4-(2-isopropylsulfinylethyl)-                              0.22    benzyl]-3-(2,4-difluorophenyl)urea    1-(n-Heptyl)-1-[4-(isopentyloxymethyl)benzyl]-                              0.33    3-(2,4-difluorophenyl)urea    1-(n-Heptyl)-1-[4-(isopentyloxymethyl)benzyl]-                              0.18    3-(2,4,6-trifluorophenyl)urea    1-(n-Heptyl)-1-[4-isopentyloxymethyl)benzyl]-                              0.13    3-(4-chloro-2,6-dimethylphenyl)urea    ______________________________________

Inhibition of cholesterol absorption was determined by feeding maleSprague-Dawley rats, weighing 150-170 g, a 1% cholesterol:0.5% cholicacid diet for 2 weeks. The diet also contained compounds being tested ata dose of 0.001, 0.003, 0.01, or 0.03% of the diet. Control rats werefed the same diet without any compound. At the end of the test, the ratswere sacrificed by decapitation. Blood was collected, centrifuged at 1.5times gravity for 10 minutes at 4° C.; and the serum was then analyzedfor cholesterol and triglycerides enzymatically by the method ofTrinder, P., Analyst, 77, 321 (1952) on a Centrifichem 400 analyzer.Livers were removed, a 0.4 g sample was taken from the center of thelarge lobe, and the sample was subjected to saponification using 25%saturated potassium hydroxide in ethanol. The resulting neutral sterolswere extracted with petroleum ether and the extract analyzed forcholesterol. The effectiveness of the compound in inhibiting cholesterolabsorption was measured by the lowering of either serum cholesterol orliver cholesterol relative the values for control rats.

Compounds which produced statistically significant inhibition ofcholesterol absorption are considered to be active. Liver sterol (LS)and serum sterol (SS) values are expressed as a percentage of controlvalues. The results of this test on typical compounds of this inventionappear in Table IV.

                  TABLE IV    ______________________________________                           Dose    Compound               %       LS     SS    ______________________________________    1-Benzyl-1-(n-butyl)-3-(2,4-dimethylphen-                           .03     65     70    yl)urea    1-Benzyl-1-(n-butyl)-3-(2,6-dimethylphen-                           .03     91     68    yl)urea    1-Benzyl-1-(n-butyl)-3-(3,5-dimethylphen-                           .03     75     93    yl)urea    1-Benzyl-1-(1,2-diphenylethyl)-3-(2,4-                           .03     63     52    dimethylphenyl)urea    1-(2-Fluorobenzyl)-1-(2-methoxybenzyl)-3-                           .03     20     45    (2,4-dimethylphenyl)urea    1-(n-Butyl)-1-(4-hexyloxybenzyl)-3-(2,4-                           .03     15     54    trimethylphenyl)urea    1-(n-Butyl)-1-(4-heptyloxybenzyl)-3-                           .03     31     66    (2,4,6-trimethylphenyl)urea    1-Benzyl-1-(4-n-butylbenzyl)-3-(2,4-                           .03     20     41    dimethylphenyl)urea    1-Benzyl-1-(4-n-butylbenzyl)-3-(2,4,6-                           .03     13     53    trimethylphenyl)urea    1-Benzyl-1-(4-n-butylbenzyl)-3-(4-n-butyl-                           .03     61     53    phenyl)urea    1-(n-Heptyl)-1-(4-n-butylbenzyl)-3-(2,4-                           .03     14     46    dimethylphenyl)urea    1-(n-Heptyl)-1-(4-n-butylbenzyl)-3-(2,4,5-                           .03     10     33    trimethylphenyl)urea    1-(n-Heptyl)-1-(4-butyloxybenzyl)-3-(2,4-                           .03     22     26    dimethylphenyl)urea    1-(n-Heptyl)-1-(4-butyloxybenzyl)-3-                           .03     17     32    (2,4,5-trimethylphenyl)urea    1-Benzyl-1-(4-butyloxybenzyl)-3-(2,4-                           .03     15     48    dimethylphenyl)urea    1-Benzyl-1-(4-butyloxybenzyl)-3-(2,4,5-                           .03     12     43    trimethylphenyl)urea    1-Benzyl-1-(4-n-butylbenzyl)-3-(2,4,5-                           .03     10     50    trimethylphenyl)urea    1-Benzyl-1-[2-phenyl-1-(4-benzyloxy-                           .03     49     60    phenyl)ethyl]-3-(2,4,6-trimethylphenyl)-    urea    1-(n-Heptyl)-1-(4-n-butoxybenzyl)-3-                           .03     11     35    (2,4,6-trichlorophenyl)urea    1-(n-Heptyl)-(4-n-butoxybenzyl)-3-(2,4-                           .03     50     68    dichlorophenyl)urea    1-(n-Heptyl)-(4-n-butoxybenzyl)-3-(2-tri-                           .03     35     59    fluoromethyl-4-chlorophenyl)urea    1-Benzyl-1-(4-n-butoxybenzyl)-3-(2,4,6-                           .03     8      40    trichlorophenyl)urea    1-Benzyl-1-(4-n-butoxybenzyl)-3-(2,4-                           .03     49     53    dichlorophenyl)urea    1-Benzyl-1-(4-n-butoxybenzyl)-3-(2-tri-                           .03     31     58    fluoromethyl-4-chlorophenyl)urea    1-(n-Heptyl)-1-(4-n-butoxybenzyl)-3-(3-                           .03     86     80    trifluoromethylphenyl)urea    1-(n-Heptyl)-1-(4-n-butylbenzyl)-3-(2,4-                           .03     50     58    dichlorophenyl)urea    1-(n-Heptyl)-1-(4-n-butylbenzyl)-3-(2-                           .03     47     63    trifluoromethyl-4-chlorophenyl)urea    1-(n-Heptyl)-1-(4-butylbenzyl)-3-(2,4,6-                           .03     8      28    trichlorophenyl)urea    1-Benzyl-1-(4-n-butylbenzyl)-3-(2-methyl-                           .03     21     70    4-chlorophenyl)urea    1-(n-Heptyl)-1-(4-n-butoxybenzyl)-3-(2,4-                           .03     25     63    difluorophenyl)urea    1-(n-Heptyl)-1-(4-n-butoxybenzyl)-3-(2-                           .03     15     53    methyl-4-chlorophenyl)urea    1-(n-Heptyl)-1-(4-n-butylbenzyl)-3-(2-                           .03     16     35    methyl-4-chlorophenyl)urea    1-(n-Heptyl)-1-(4-n-butylbenzyl)-3-(2,4-                           .03     19     35    difluorophenyl)urea    1-(n-Heptyl)-1-(4-n-butylbenzyl)-3-(4-                           .03     84     88    carboethoxyphenyl)urea    1-(n-Heptyl)-1-(4-n-butylbenzyl)-3-(2-                           .03     29     35    methylphenyl)urea    1-(n-Heptyl)-1-(4-n-butylbenzyl)-3-(3-                           .03     42     49    methylphenyl)urea    1-(n-Heptyl)-1-(2-phenylethyl)-3-(2-                           .03     49     66    methyl-4-chlorophenyl)urea    1-(n-Heptyl)-1-(2-phenylethyl)-3-(2-                           .03     80     79    trifluoromethyl-4-chlorophenyl)urea    1-(n-Heptyl)-1-(2-phenylethyl)-3-(2,4-                           .03     36     57    dimethylphenyl)urea    1-(n-Heptyl)-1-(2-phenylethyl)-3-(2,4-di-                           .03     88     81    chlorophenyl)urea    1-(n-Heptyl)-1-(2-phenylethyl)-3-(2,4-                           .03     57     59    difluorophenyl)urea    1-Benzyl-1-[2-phenyl-1-(4-benzyloxyphen-                           .03     64     95    yl)ethyl]-3-(2,4,6-trichlorophenyl)urea    1-(4-n-Pentylbenzyl)-1-(4-n-pentyloxy-                           .03     76     100    benzyl)-3-(2,4,6-trichlorophenyl)urea    1-(4-n-Pentylbenzyl)-1-(4-n-pentyloxy-                           .03     92     91    benzyl)-3-(2,4-dichlorophenyl)urea    1-(4-n-Pentylbenzyl)-1-(4-n-pentyloxy-                           .03     92     85    benzyl)-3-(2,4,5-trichlorophenyl)urea    1-(4-n-Pentylbenzyl)-1-(4-n-pentyloxy-                           .03     67     55    benzyl)-3-(2,4-difluorophenyl)urea    1-(4-Chlorobenzyl)-1-(1-naphthylmethyl)-3-                           .03     12     38    (2,4,6-trichlorophenyl)urea    1-(4-Chlorobenzyl)-1-(1-naphthylmethyl)-                           .03     17     35    3-(2-methyl-4-chlorophenyl)urea    1-(4-Chlorobenzyl)-1-(1-naphthylmethyl)-3-                           .03     30     45    (2,4-difluorophenyl)urea    1-(4-Chlorobenzyl)-1-(1-naphthylmethyl)-3-                           .03     92     87    (3-trifluoromethylphenyl)urea    1-(4-Chlorobenzyl)-1-(1-naphthylmethyl)-3-                           .03     97     84    (2,4,5-trichlorophenyl)urea    1-Benzyl-1-(4-n-butyloxybenzyl)-3-(2,4,5-                           .03     65     66    trichlorophenyl)urea    1-Benzyl-1-[2-phenyl-1-(4-benzyloxy-                           .03     27     48    phenyl)-ethyl]-3-(2,4-difluorophenyl)urea    1-Benzyl-1-(4-n-butoxybenzyl)-3-(2,4-di-                           .03     22     53    fluorophenyl)urea    1-Benzyl-1-[2-phenyl-1-(4-benzyloxy-                           .03     31     50    phenyl)ethyl]-3-(2-methyl-4-chlorophenyl)-    urea    1-(4-Chlorobenzyl)-1-(1-naphthylmethyl)-                           .03     48     50    3-(2,4-dichlorophenyl)urea    1-[(4-Butylphenyl)methyl]-1-(6-hydroxy-                           .03     39     57    hexyl)-3-(2,4,5-trimethylphenyl)urea    1-[(4-Butylphenyl)methyl]-1-[2-(2-hydroxy-                           .03     76     100    ethoxy)ethyl]-3-(2,4,5-trimethylphenyl)-    urea    1-(2-Furanylmethyl)-1-heptyl-3-(2,4,5-                           .03     38     44    trimethylphenyl)urea    1-(2-Furanylmethyl)-1-heptyl-3-(2,4,6-                           .03     34     37    trichlorophenyl)urea    1-Heptyl-1-(2-thienylmethyl)-3-(2,4,5-                           .03     25     54    trimethylphenyl)urea    1-Heptyl-1-(2-thienylmethyl)-3-(2,4,6-                           .03     28     56    trichlorophenyl)urea    1-[(4-Butoxyphenyl)methyl]-1-(2-thienyl-                           .03     16     41    methyl)-3-(2,4,5-trimethylphenyl)urea    1-[(4-Butylphenyl)methyl]-1-(6-cyano-                           .03     28     48    hexyl)-3-(2,4,5-trimethylphenyl)urea    1-[(4-Butylphenyl)methyl]-1-(6-chloro-                           .03     15     40    hexyl)-3-(2,4,5-trimethylphenyl)urea    1-[(4-Butylphenyl)methyl]-3-(4-chloro-2-                           .03     53     6    methylphenyl)-1-(6-hydroxyhexyl)urea    1-[(4-Butylphenyl)methyl]-3-(4-chloro-2-                           .03     50     48    methylphenyl)-1-(6-cyanohexyl)urea    1-[(4-Butylphenyl)methyl]-1-(6-chloro-                           .03     35     46    hexyl)-3-(4-chloro-2-methylphenyl)urea    1-[(4-Butylphenyl)methyl]-1-(6-hydroxy-                           .03     32     35    hexyl)-3-(2,4,6-trichlorophenyl)urea    1-[(4-Butylphenyl)methyl]-1-(6-cyano-                           .03     35     31    hexyl)-3-(2,4,6-trichlorophenyl)urea    1-[(4-Butylphenyl)methyl]-1-(6-chloro-                           .03     19     34    hexyl)-3-(2,4,6-trichlorophenyl)urea    1-[(4-Butylphenyl)methyl]-3-(4-chloro-2-                           .03     62     50    methylphenyl)-1-[5-(trimethylsilyl)-    pentyl]urea    1-[(4-Butylphenyl)methyl]-3-(2,4-difluoro-                           .03     57     62    phenyl)-1-[5-(trimethylsilyl)pentyl]urea    3-(2,4-Difluorophenyl)-1-(3,3-dimethyl-                           .03     73     66    butyl)-1-(2-thienylmethyl)urea    3-(4-Chloro-2-methylphenyl)-1-(3,3-di-                           .03     64     62    methylbutyl)-1-(2-thienylmethyl)urea    1-(3,3-Dimethylbutyl)-1-(2-thienylmethyl)-                           .03     56     58    3-(2,4,6-trichlorophenyl)urea    1-[2-(4-Methylphenyl)ethyl]-1-(3-chloro-                           .03     20     50    benzyl)-3-(2,4-dimethylphenyl)urea    1-(4-Phenylbenzyl)-1-(3,4-dichloro-                           .03     17     49    benzyl)-3-(2,4-dimethylphenyl)urea    1-(3,4-Dimethylbenzyl)-1-(2-chlorobenzyl)-                           .03     15     44    3-(2,4-dimethylphenyl)urea    1-(n-Butyl)-1-benzyl-3-(2,4,6-trichloro-                           .03     32     48    phenyl)urea    1-(n-Butyl)-1-benzyl-3-(4-chloro-2-methyl-                           .03     62     72    phenyl)urea    1-(3,3-Dimethylbutyl)-1-[4-(n-butyl)-                           .03     13     46    benzyl]-3-(4-chloro-2-methylphenyl)urea    1-(3,3-Dimethylbutyl)-1-[4-(n-butoxy)-                           .03     22     61    benzyl]-3-(4-chloro-2-methylphenyl)urea    1-(3,3-Dimethylbutyl)-1-[4-(n-butoxy)-                           .03     20     52    benzyl]-3-(2,4,6-trichlorophenyl)urea    1-(3,3-Dimethylbutyl)-1-[4-(n-butoxy)-                           .03     32     42    benzyl]-3-(2,4-difluorophenyl)urea    1-(3,3-Dimethylbutyl)-1-[4-(n-butyl)-                           .03     30     39    benzyl]-3-(2,4-difluorophenyl)urea    1-(3,3-Dimethylbutyl)-1-[4-(n-butyl)-                           .03     13     37    benzyl]-3-(2,4,6-trichlorophenyl)urea    1-(5,5-Dimethylhexyl)-1-[4-(n-butyl)-                           .03     34     42    benzyl]-3-(4-chloro-2-methylphenyl)urea    1-(5,5-Dimethylhexyl)-1-[4-(n-butyl)-                           .03     58     59    benzyl]-3-(2,4-difluorophenyl)urea    1-(5,5-Dimethylhexyl)-1-[4-(n-butyl)-                           .03     32     45    benzyl]-3-(2,4,6-trichlorophenyl)urea    1-(3,3-Dimethylbutyl)-1-(4-chlorobenzyl)-                           .03     60     50    3-(4-chloro-2-methylphenyl)urea    1-(3,3-Dimethylbutyl)-1-benzyl-3-(2,4-                           .03     70     71    difluorophenyl)urea    1-(3,3-Dimethylbutyl)-1-(4-chlorobenzyl)-                           .03     41     73    3-(2,4,6-trichlorophenyl)urea    1-(n-Heptyl)-1-[4-(n-butyl)benzyl]-3-(4-                           .03     88     79    trifluoromethylphenyl)urea    1-(3,3-Dimethylbutyl)-1-[4-(n-butyl)ben-                           .03     86     100    zyl]-3-(4-trifluoromethylphenyl)urea    1-(3,3-Dimethylbutyl)-1-(4-chlorobenzyl)-                           .03     70     85    3-(4-trifluoromethylphenyl)urea    1-(3,3-Dimethylbutyl)-1-[4-(2,2-dimethyl-                           .03     19     35    propyl)benzyl]-3-(2,4-difluorophenyl)urea    1-(3,3-Dimethylbutyl)-1-[4-(2,2-dimethyl-                           .03     20     51    propyl)benzyl]-3-(4-chloro-2-methyl-    phenyl)urea    1-(3,3-Dimethylbutyl)-1-[4-(2,2-dimethyl-                           .03     15     32    propyl)benzyl]-3-(2,4,6-trichlorophenyl)-    urea    1-(3,3-Dimethylbutyl)-1-[4-(n-butyl)-                           .03     12     28    benzyl]-3-(4-chloro-2,6-dimethylphenyl)-    urea    1-(3,3-Dimethylbutyl)-1-(4-chlorobenzyl)-                           .03     25     46    3-(4-chloro-2,6-dimethylphenyl)urea    1-(n-Heptyl)-1-[4-(n-butyl)benzyl]-3-(4-                           .03     11     31    chloro-2,6-dimethylphenyl)urea    1-(3,3-Dimethylbutyl)-1-[4-(2,2-dimethyl-                           .03     11     31    propyl)benzyl]-3-(4-chloro-2,6-dimethyl-    phenyl)urea    1-(3,3-Dimethylbutyl)-1-benzyl-3-(4-                           .03     51     64    chloro-2-methylphenyl)urea    1-(n-Heptyl)-1-[4-(n-butyl)benzyl]-3-                           .03     19     48    (4-chloro-2,5-dimethylphenyl)urea    1-(3,3-Dimethylbutyl)-1-(benzyl)-3-(4-                           .03     30     55    chloro-2,5-dimethylphenyl)urea    1-(Isopentyl)-1-[4-(isopropyl)benzyl]-3-                           .03     37     49    (2,4-difluorophenyl)urea    1-(Isopentyl)-1-[4-(isopropyl)benzyl]-3-                           .03     23     23    (4-chloro-2,6-dimethylphenyl)urea    1-(Isopentyl)-1-[4-(isopropyl)benzyl]-3-                           .03     35     31    (2,4,6-trifluorophenyl)urea    1-(n-Heptyl)-1-[4-(isobutyl)benzyl]-3-                           .01     56     62    (4-chloro-2-methylphenyl)urea    1-(n-Heptyl)-1-[4-(isopropyl)benzyl]-3-                           .01     64     77    (2,4-difluorophenyl)urea    1-(n-Heptyl)-1-[4-(isopropyl)benzyl]-3-                           .01     20     35    (4-chloro-2,6-dimethylphenyl)urea    1-(n-Heptyl)-1-[4-(isopropyl)benzyl]-3-                           .01     75     60    (4-chloro-2-methylphenyl)urea    1-(n-Heptyl)-1-[4-(isopropyl)benzyl]-3-                           .01     23     40    (2,4,6-trifluorophenyl)urea    1-(n-Heptyl)-1-[4-(4-isopentyl)benzyl]-3-                           .01     17     20    (4-chloro-2-methylphenyl)urea    1-(n-Heptyl)-1-[4-(isopentyl)benzyl]-3-                           .01     10     17    (4-chloro-2,6-dimethylphenyl)urea    1-(n-Heptyl)-1-[4-(2-acetoxyethyl)benzyl]-                           .003    60     55    3-(2,4-difluorophenyl)urea    1-(n-Heptyl)-1-[4-(2-hydroxyethyl)benzyl]-                           .003    59     52    3-(2,4-difluorophenyl)urea    1-(n-Heptyl)-1-[4-(4-hydroxybutyl)benzyl]-                           .01     26     24    3-(4-chloro-2,6-dimethylphenyl)urea    1-(n-Heptyl)-1-[4-(4-chlorobutyl)benzyl]-                           .03     18     19    3-(4-chloro-2,6-dimethylphenyl)urea    1-(n-Heptyl)-1-[4-(3-carboethoxypropyl)-                           .01     65     55    benzyl]-3-(4-chloro-2,6-dimethylphenyl)-    urea    1-(n-Heptyl)-1-[4-(3-methylbutoxy)benzyl)-                           .01     32     27    3-(2,4-difluorophenyl)urea    1-(n-Heptyl)-1-[4-(4-ethylthiobutyl)-                           .003    63     57    benzyl]-3-(4-chloro-2,6-dimethylphenyl)-    urea    1-(n-Heptyl)-1-[4-(4-isopropylthiobutyl)-                           .01     45     49    benzyl]-3-(4-chloro-2,6-dimethylphenyl)-    urea    1-(Isoheptyl)-1-[4-isopentyl)benzyl)-3-                           .003    45     24    (2,4-difluorophenyl)urea    1-(Isoheptyl)-1-[4-(isopentyl)benzyl]-3-                           .001    40     40    (4-chloro-2,6-dimethylphenyl)urea    1-(Isoheptyl)-1-[4-(isopentyl)benzyl]-3-                           .001    45     33    (2,4,6-trifluorophenyl)urea    1-(n-Heptyl)-1-[4-(2-ethylhexyl)benzyl]-3-                           .001    87     82    (2,4,6-trifluorophenyl)urea    1-(n-Heptyl)-1-[4-(2-ethylhexyl)benzyl]-3-                           .001    87     83    (4-chloro-2,6-dimethylphenyl)urea    1-(n-Heptyl)-1-[4-(2-ethylbutyl)benzyl]-3-                           .003    98     66    (2,4-difluorophenyl)urea    1-(n-Heptyl)-1-[4-(2-ethylbutyl)benzyl]-3-                           .001    75     120    (2,4,6-trifluorophenyl)urea    1-(n-Heptyl)-1-[4-(isohexyl)benzyl]-3-                           .003    53     45    (2,4-difluorophenyl)urea    1-(n-Heptyl)-1-[4-(isohexyl)benzyl]-3-                           .001    73     64    (4-chloro-2,6-dimethylphenyl)urea    1-(n-Heptyl)-1-[4-(isohexyl)benzyl]-3-                           .001    78     77    (2,4,6-trifluorophenyl)urea    1-(n-Heptyl)-1-[4-(cyclopentyl)benzyl]-3-                           .003    82     80    (2,4-difluorophenyl)urea    1-(n-Heptyl)-1-[4-(cyclopentyl)benzyl]-3-                           .003    36     35    (4-chloro-2,6-dichlorophenyl)urea    1-(n-Heptyl)-1-[4-(2-ethylhexyl)benzyl]-3-                           .003    56     63    (2,4-difluorophenyl)urea    1-(n-Heptyl)-1-[4-(cyclopentyl)benzyl]-3-                           .001    58     69    (2,4,6-trifluorophenyl)urea    1-(n-Heptyl)-1-[4-(2-ethylbutyl)benzyl]-3-                           .001    94     62    (4-chloro-2,6-dimethylphenyl)urea    1-(n-Heptyl)-1-[4-(2-methylpentyl)benzyl]-                           .003    72     53    3-(2,4-difluorophenyl)urea    1-(n-Heptyl)-1-[4-(2-methylpentyl)benzyl]-                           .001    75     93    3-(2,4,6-trifluorophenyl)urea    1-(n-Heptyl)-1-[4-(2-methylpentyl)benzyl]-                           .001    56     61    3-(4-chloro-2,6-dimethylphenyl)urea    1-(n-Heptyl)-1-[4-(3-methylpentyl)benzyl]-                           .001    89     72    3-(2,4-difluorophenyl)urea    1-(n-Heptyl)-1-[4-(3-methylpentyl)benzyl]-                           .003    46     36    3-(2,4,6-trifluorophenyl)urea    1-(n-Heptyl)-1-[4-(3-methylpentyl)benzyl]-                           .003    45     38    3-(4-chloro-2,6-dimethylphenyl)urea    1-(n-Heptyl)-1-[4-(cyclobutylmethyl)ben-                           .001    69     64    zyl]-3-(4-chloro-2,6-dimethylphenyl)urea    1-(n-Heptyl)-1-[4-(cyclopentylmethyl)ben-                           .003    50     62    zyl]-3-(2,4,6-trifluorophenyl)urea    1-(n-Heptyl)-1-[4-(cyclopentylmethyl)ben-                           .01     80     --    zyl]-3-(2,4-difluorophenyl)urea    1-(n-Heptyl)-1-[4-(cyclobutylmethyl)ben-                           .001    66     62    zyl]-3-(2,4,6-trifluorophenyl)urea    1-(n-Heptyl)-1-[4-(1,5-dimethylhexyl)ben-                           .001    88     83    zyl]-3-(2,4-difluorophenyl)urea    1-(n-Heptyl)-1-[4-(1,5-dimethylhexyl)ben-                           .001    100    94    zyl]-3-(4-chloro-2,6-dimethylphenyl)urea    1-(n-Heptyl)-1-[4-(1,5-dimethylhexyl)ben-                           .003    65     57    zyl]-3-(2,4,6-trifluoromethylphenyl)urea    1-(n-Heptyl)-1-[4-(cyclopentylmethyl)ben-                           .003    53     45    zyl]-3-(4-chloro-2,6-dimethylphenyl)urea    1-(n-Heptyl)-1-[4-(hydroxymethyl)benzyl]-                           .003    81     --    3-(2,4-difluorophenyl)urea    1-(n-Heptyl)-1-[ 4-(acetoxymethyl)benzyl]-                           .01     70     --    3-(2,4-difluorophenyl)urea    1-(n-Heptyl)-1-[4-(isopentyloxy)benzyl]-3-                           .001    23     25    (4-chloro-2,6-dimethylphenyl)urea    1-(n-Heptyl)-1-[4-(isopentyloxy)benzyl]-3-                           .001    61     69    (2,4-difluorophenyl)urea    1-(n-Heptyl)-1-[4-(2-methylbutyl)benzyl]-                           .01     42     36    3-(2,4-difluorophenyl)urea    1-(n-Heptyl)-1-[4-(2-methylbutyl)benzyl]-                           .001    64     76    3-(2,4,6-trifluorophenyl)urea    1-(n-Heptyl)-1-[4-(2-isopropylthioethyl)-                           .003    51     49    benzyl]-3-(4-chloro-2,6-dimethylphenyl)-    urea    1-(n-Heptyl)-1-[4-(2-isopropylsulfonyl-                           .003    68     94    ethyl)benzyl]-3-(2,4-difluorophenyl)urea    1-(n-Heptyl)-1-[4-(2-isopropylsulfonyl-                           .003    54     57    ethyl)benzyl]-3-(4-chloro-2,6-dimethyl-    phenyl)urea    1-(n-Heptyl)-1-[4-(2,3-dimethylpentyl)-                           .01     63     48    benzyl]-3-(2,4-difluorophenyl)urea    1-(n-Heptyl)-1-[4-(2-isopropylthioethyl)-                           .003    72     --    benzyl]-3-(2,4-difluorophenyl)urea    1-(n-Heptyl)-1-[4-(2-isopropylsulfinyl-                           .003    54     45    ethyl)benzyl]-3-(4-chloro-2,6-dimethyl-    phenyl)urea    1-(n-Heptyl)-1-[4-(2,3-dimethylpentyl)-                           .01     31     33    benzyl]-3-(2,4,6-trifluorophenyl)urea    1-(n-Heptyl)-1-[4-(2,2-dimethylpropyl)-                           .01     51     22    benzyl]-3-(2,4-difluorophenyl)urea    1-(n-Heptyl)-1-[4-(2,2-dimethylpropyl)-                           .003    55     38    benzyl]-3-(2,4,6-trifluorophenyl)urea    1-(n-Heptyl)-1-[4-(2,2-dimethylpropyl)-                           .003    54     41    benzyl]-3-(4-chloro-2,6-dimethylphenyl)-    urea    1-(n-Heptyl)-1-[4-(2,3-dimethylpentyl)-                           .01     40     43    benzyl]-3-(4-chloro-2,6-dimethylphenyl)-    urea    1-(n-Heptyl)-1-[4-(2-isopropylsulfinyl-                           .003    84     --    ethyl)benzyl]-3-(2,4-difluorophenyl)urea    1-(n-Heptyl)-1-[4-(isopentyloxymethyl)-                           .01     60     --    benzyl]-3-(2,4-difluorophenyl)urea    1-(n-Heptyl)-1-[4-(isopentyloxymethyl)-                           .001    75     --    benzyl]-3-(2,4,6-trifluorophenyl)urea    1-(n-Heptyl)-1-[4-(isopentyloxymethyl)-                           .003    47     --    benzyl]-3-(4-chloro-2,6-dimethylphenyl)-    urea    ______________________________________

The tests reported or shown in Table I, II, III and IV, inclusive, havebeen actually carried out and the results therein actually obtained orconcluded therefrom.

When the compounds are employed for the above utility, they may becombined with one or more pharmaceutically acceptable carriers, e.g.,solvents, diluents, and the like, and may be administered orally in suchforms as tablets, capsules, dispersible powders, granules, orsuspensions containing, for example, from about 0.5% to 5% of suspendingagent, syrups containing, for example, from about 10% to 50% of sugar,and elixirs containing, for example, from about 20% to 50% ethanol, andthe like, or parenterally in the form of sterile injectable solutions orsuspensions containing from about 0.5% to 5% suspending agent in anisotonic medium. These pharmaceutical preparations may contain, forexample, from about 0.5% up to about 90% of the active ingredient incombination with the carrier, more usually between 5% and 60% by weight.

The antiatherosclerotic effective dosage of active ingredient employedmay vary depending on the particular compound employed, the mode ofadministration, and the severity of the condition being treated. Ingeneral, however, satisfactory results are obtained when the compoundsof the invention are administered at a daily dosage of from about 2 mgto about 500 mg/kg of animal body weight, preferably given in divideddoses two to four times a day, or in sustained release form. For mostlarge mammals, the total daily dosage is from about 100 mg to about5,000 mg, preferably from about 100 mg to 2,000 mg. Dosage formssuitable for internal use comprise from about 25 to 500 mg of the activecompound in intimate admixture with a solid or liquid pharmaceuticallyacceptable carrier. This dosage regimen may be adjusted to provide theoptimal therapeutic response. For example, several divided doses may beadministered daily or the dose may be proportionally reduced asindicated by the exigencies of the therapeutic situation. A decidedpractical advantage is that these active compounds may be administeredorally as well as by intravenous, intramuscular, or subcutaneous routesif necessary. Solid carriers include starch, lactose, dicalciumphosphate, microcrystalline cellulose, sucrose, and kaolin, while liquidcarriers include sterile water, polyethylene glycols, non-ionicsurfactants, and edible oils such as corn, peanut, and sesame oils, asare appropriate to the nature of the active ingredient and theparticular form of administration desired. Adjuvants customarilyemployed in the preparation of pharmaceutical compositions may beadvantageously included, such as flavoring agents, coloring agents,preserving agents, and antioxidants, e.g., vitamin E, ascorbic acid,BHT, and BHA.

The preferred pharmaceutical compositions from the stand-point of easeof preparation and administration are solid compositions, particularlytablets and hard-filled or liquid-filled capsules. Oral administrationof the compounds is preferred.

These active compounds may also be administered parenterally orintraperitoneally. Solutions or suspensions of these active compounds asa free base or pharmacologically acceptable salt can be prepared inwater suitably mixed with a surfactant such as hydroxypropylcellulose.Dispersions can also be prepared as glycerol, liquid polyethyleneglycols, and mixtures thereof in oils. Under ordinary conditions ofstorage and use, these preparations contain a preservative to preventthe growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form must be sterile and must be fluid tothe extent that easy syringability exists. It must be stable under theconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent of dispersion medium containing, for example,water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquidpolyethylene glycol), suitable mixtures thereof, and vegetable oils.

The following examples describe in detail the chemical synthesis ofrepresentative compounds of the present invention. The procedures areillustrations, and the invention should not be construed as beinglimited by chemical reactions and conditions they express. No attempthas been made to optimize the yields obtained in these reactions, and itwould be obvious to one skilled in the art that variations in reactiontimes, temperatures, solvents, and/or reagents could increase theyields.

EXAMPLE 1 1-Benzyl-1-(n-butyl)-3-(2,4-dimethylphenyl)urea

A solution of 4.89 g of 2,4-dimethylphenylisocyanate in 100 ml of hexaneis added to a solution of 4.41 g of N-benzyl-n-butylamine in 150 ml ofhexane, and the solution is stirred at room temperature for 2 hours andthen evaporated. The residual solid is recrystallized from pentane toyield 1-benzyl-1-(n-butyl)-3-(2,4-dimethylphenyl)urea, m.p. 70°-71° C.

With reference to Example 1 and Table V, only those examples with listedcharacteristics have been actually carried out. All other examples aresimulated or predicted.

                                      TABLE V    __________________________________________________________________________    Example         Compound                           M.P. °C.    __________________________________________________________________________     2   1-Benzyl-1-( -n-butyl)-3-(2-methylphenyl)urea                                            48-53     3   1-Benzyl-1-( -n-butyl)-3-(3-methylphenyl)urea                                            91-92     4   1-Benzyl-1-( -n-butyl)-3-(4-methylphenyl)urea                                            102-103     5   1-Benzyl-1-( -n-butyl)-3-(3-ethylphenyl)urea     6   1-Benzyl-1-( -n-butyl)-3-(4-ethylphenyl)urea     7   1-Benzyl-1-( -n-butyl)-3-(4-isopropylphenyl)urea     8   1-Benzyl-1-( -n-butyl)-3-(4- -n-butylphenyl)urea     9   1-Benzyl-1-( -n-butyl)-3-(2,3-dimethylphenyl)urea                                            77-78     10  1-Benzyl-1-( -n-butyl)-3-(2,5-dimethylphenyl)urea                                            87-89     11  1-Benzyl-1-( -n-butyl)-3-(2,6-dimethylphenyl)urea                                            125-126     12  1-Benzyl-1-( -n-butyl)-3-(3,4-dimethylphenyl)urea                                            94-95     13  1-Benzyl-1-( -n-butyl)-3-(3,5-dimethylphenyl)urea                                            108-109     14  1-Benzyl-1-( -n-butyl)-3-(2,4,5-trimethylphenyl)urea     15  1-Benzyl-1-( -n-butyl)-3-(2,4,6-trimethylphenyl)urea                                            141-144     16  1-Benzyl-1-( -n-butyl)-3-(4-methoxyphenyl)urea     17  1-Benzyl-1-( -n-butyl)-3-(4- -n-butoxyphenyl)urea     18  1-Benzyl-1-( -n-butyl)-3-(3,4,5-trimethoxyphenyl)urea                                            144-145     19  1-Benzyl-1-( -n-butyl)-3-(4-methylthiophenyl)urea     20  1-Benzyl-1-( -n-butyl)-3-(2-chlorophenyl)urea     21  1-Benzyl-1-( -n-butyl)-3-(4-chlorophenyl)urea     22  1-Benzyl-1-( -n-butyl)-3-(2-bromophenyl)urea     23  1-Benzyl-1-( -n-butyl)-3-(4-bromophenyl)urea     24  1-Benzyl-1-(  -n-butyl)-3-(4-fluorophenyl)urea     25  1-Benzyl-1-( -n-butyl)-3-(4-iodophenyl)urea     26  1-Benzyl-1-( -n-butyl)-3-(2,3-dichlorophenyl)urea     27  1-Benzyl-1-( -n-butyl)-3-(2,4-dichlorophenyl)urea     28  1-Benzyl-1-( -n-butyl)-3-(2,5-dichlorophenyl)urea     29  1-Benzyl-1-( -n-butyl)-3-(3,4-dichlorophenyl)urea                                            102-105     30  1-Benzyl-1-( -n-butyl)-3-(3,5-dichlorophenyl)urea                                            100-103     31  1-Benzyl-1-( -n-butyl)-3-(2,4,6-trichlorophenyl)urea                                            94-96     32  1-Benzyl-1-( -n-butyl)-3-(2,4-difluorophenyl)urea     33  1-Benzyl-1-( -n-butyl)-3-(3-trifluoromethylphenyl)urea                                            86-87     34  1-Benzyl-1-( -n-butyl)-3-(3-acetylphenyl)urea     35  1-Benzyl-1-( -n-butyl)-3-(4-acetylphenyl)urea     36  1-Benzyl-1-( -n-butyl)-3-(4-carboethoxyphenyl)urea     37  1-Benzyl-1-( -n-butyl)-3-(4-phenoxyphenyl)urea     38  1-Benzyl-1-( -n-butyl)-3-(2-cyanophenyl)urea     39  1-Benzyl-1-( -n-butyl)-3-(3-chloro-2-methoxyphenyl)urea                                            52-54     40  1-Benzyl-1-( -n-butyl)-3-(5-chloro-4-methoxyphenyl)urea                                            61-63     41  1-Benzyl-1-( -n-butyl)-3-(2,6-dibromo-4-fluorophenyl)urea     42  1-Benzyl-1-( -n-butyl)-3-(2-nitro-4-methylphenyl)urea     43  1-Benzyl-1-( -n-butyl)-3-(3-chloro-4-methylphenyl)urea                                            yellow oil     44  1-Benzyl-1-( -n-butyl)-3-(4-chloro-3-trifluoromethylphenyl)urea     45  1-Benzyl-1-( -n-butyl)-3-(4-chloro-3-trifluoromethylphenyl)urea     46  1-Benzyl-1-( -n-butyl)-3-(2-chloro-5-trifluoromethylphenyl)urea     47  1-Benzyl-1-( -n-butyl)-3-(3,4-methylenedioxyphenyl)urea     48  1-Benzyl-1-( -n-butyl)-3-(4-phenylphenyl)urea     49  1-Benzyl-1-( -n-butyl)-3-(4-benzylphenyl)urea     50  1-Benzyl-1-(sec-butyl)-3-(2,4-dimethylphenyl)urea     51  1-Benzyl-1-(tert-butyl)-3-(4-methylphenyl)urea     52  1-Benzyl-1-( -n-hexyl)-3-(4-ethylphenyl)urea     53  1-Benzyl-1-( -n-heptyl)-3-(2-methylphenyl)urea     54  1-Benzyl-1-( -n-octyl)-3-(2-methylphenyl)urea     55  1-Benzyl-1-( -n-nonyl)-3-(4-carboethoxyphenyl)urea     56  1-Benzyl-1-( -n-undecyl)-3-(2-methylphenyl)urea     57  1-Benzyl-1-( -n-tridecyl)-3-(methylphenyl)urea     58  1-Benzyl-1-( -n-tetradecyl)-3-(2-methylphenyl)urea     59  1-Benzyl-1-( -n-hexadecyl)-3-(2-methylphenyl)urea     60  1-Benzyl-1-( -n-octadecyl)-3-(3-chlorophenyl)urea     61  1-(2-Phenylethyl)-1-(sec-butyl)-3-(2,4-dimethylphenyl)urea     62  1-(2-Phenylethyl)-1-( -n-hexyl)-3-(3-chloro-4-methylphenyl)urea     63  1-(2-Phenylethyl)-1-( -n-heptyl)-3-(4-chlorophenyl)urea     64  1-(2-Phenylethyl)-1-( -n-octyl)-3-(4-carboethoxyphenyl)urea     65  1-(2-Phenylethyl)-1-( -n-nonyl)-3-(2,4-dimethylphenyl)urea     66  1-(2-Phenylethyl)-1-( -n-decyl)-3-(2,4-dichlorophenyl)urea     67  1-(2-Phenylethyl)-1-( -n-undecyl)-3-(3-methylphenyl)urea     68  1-(2-Phenylethyl)-1-( -n-tridecyl)-3-(2-chlorophenyl)urea     69  1-(2-Phenylethyl)-1-( -n-hexadecyl)-3-(4-methylphenyl)urea     70  1-(4-Phenyl- -n-butyl)-1-( -n-hexyl)-3-(3-methylphenyl)urea     71  1-(4-Phenyl- -n-butyl)-1-( -n-heptyl)-3-(2,4-dimethylphenyl)urea     72  1-(4-Phenyl- -n-butyl)-1-(   -n-octyl)-3-(4-methylphenyl)urea     73  1-(4-Phenyl- -n-butyl)-1-( -n-nonyl)-3-(2,4-dichlorophenyl)urea     74  1-(4-Phenyl- -n-butyl)-1-( -n-decyl)-3-(3-chloro-4-methylphenyl)urea     75  1-(4-Phenyl- -n-butyl)-1-( -n-undecyl)-3-(4-chlorophenyl)urea     76  1-(4-Phenyl- -n-butyl)-1-( -n-dodecyl)-3-(3-chlorophenyl)urea     77  1-(4-Phenyl- -n-butyl)-1-( -n-tetradecyl)-3-(3-methylphenyl)urea     78  1-(4-Phenyl- -n-butyl)-1-( -n-octadecyl)-3-(2,4-dimethylphenyl)urea     79  1-Benzyl-1-(1,2-diphenylethyl)-3-(2,4-dimethylphenyl)urea                                            157-158     80  1-Benzyl-1-[1-(3-methoxyphenyl)-2-phenylethyl]-3-(2,4-dimethylphenyl)         -                                  124-126         urea     81  1-Benzyl-1-[1-(4-benzyloxyphenyl)-2-phenyl]-3-(2,4-dimethylphenyl)-                                            140-141         urea     82  N--(2,4-dimethylphenyl)-3,4-dihydro-1-(phenylmethyl)-2(1H)-isoquino-         linecarboxamide     83  1-Benzyl-1-[1-(3-methoxyphenyl)-2-phenylethyl]-3-(3-trifluoromethyl-                                            125-126         phenyl)urea     84  1-Benzyl-1-(2-phenylethyl)-3-(2,4-dimethylphenyl)urea     85  1-Benzyl-1-(4-phenyl- -n-butyl)-3-(2,4-dimethylphenyl)urea     86  1-Benzyl-1-( -n-pentyl)-3-(2,4-dimethylphenyl)urea                                            oil     87  1-Benzyl-1-( -n-hexyl)-3-(2,4-dimethylphenyl)urea                                            oil     88  1-Benzyl-1-( -n-octyl)-3-(2,4-dimethylphenyl)urea                                            oil     89  1-Benzyl-1-( -n-undecyl)-3-(2,4-dimethylphenyl)urea                                            oil     90  1-Benzyl-1-(4-cyclohexyl- -n-butyl)-3-(2,4-dimethylphenyl)urea     91  1-Benzyl-1-(cyclopentyl)-3-(2,4-dimethylphenyl)urea     92  1-Benzyl-1-(1-naphthylmethyl)-3-(2,4-dimethylphenyl)urea     93  1-Benzyl-1-(3-chlorobenzyl)-3-(2,4-dimethylphenyl)urea     94  1-Benzyl-1-(4-chlorobenzyl)-3-(2,4-dimethylphenyl)urea     95  1-Benzyl-1-[2-(4-chlorophenyl)ethyl]-3-(2,4-dimethylphenyl)urea     96  1-Benzyl-1-(2,4-dichlorobenzyl)-3-(2,4-dimethylphenyl)urea     97  1-Benzyl-1-(4-methoxybenzyl)-3-(2,4-dimethylphenyl)urea     98  1-Benzyl-1-[2-(2-methoxyphenyl)ethyl]-3-(2,4-dimethylphenyl)urea     99  1-Benzyl-1-(4-methylbenzyl)-3-(2,4-dimethylphenyl)urea    100  1-Benzyl-1-(3-methylbenzyl)-3-(2,4-dimethylphenyl)urea    101  1-Benzyl-1-[2-(4-methylphenyl)ethyl]-3-(2,4-dimethylphenyl)urea    102  1-Benzyl-1-(2-phenylethyl)-3-(3-chloro-4-methylphenyl)urea    103  1-Benzyl-1-(4-phenyl- -n-butyl)-3-(3-chloro-4-methylphenyl)urea    104  1-Benzyl-1-( -n-heptyl)-3-(3-chloro-4-methylphenyl)urea    105  1-Benzyl-1-( -n-octyl)-3-(3-chloro-4-methylphenyl)urea    106  1-Benzyl-1-( -n-decyl)-3-(3-chloro-4-methylphenyl)urea    107  1-Benzyl-1-( -n-undecyl)-3-(3-chloro-4-methylphenyl)urea    108  1-Benzyl-1-( -n-tridecyl)-3-(3-chloro-4-methylphenyl)urea    109  1-Benzyl-1-( -n-tetradecyl)-3-(3-chloro-4-methylphenyl)urea    110  1-Benzyl-1-( -n-hexadecyl)-3-(3-chloro-4-methylphenyl)urea    111  1-Benzyl-1-( -n-octadecyl)-3-(3-chloro-4-methylphenyl)urea    112  1-Benzyl-1-(cyclohexyl)-3-(3-chloro-4-methylphenyl)urea    113  1-Benzyl-1-(1-naphthylmethyl)-3-(3-chloro-4-methylphenyl)urea    114  1-Benzyl-1-(4-chlorobenzyl)-3-(3-chloro-4-methylphenyl)urea    115  1-Benzyl-1-(4-methylbenzyl)-3-(3-chloro-4-methylphenyl)urea    116  1-Benzyl-1-( -n-hexyl)-3-(4-methylphenyl)urea    117  1-Benzyl-1-( -n-octyl)-3-(4-methylphenyl)urea    118  1-Benzyl-1-( -n-undecyl)-3-(4-methylphenyl)urea    119  1-Benzyl-1-( -n-tetradecyl)-3-(4-methylphenyl)urea    120  1-Benzyl-1-( -n-hexadecyl)-3-(4-methylphenyl)urea    121  1-Benzyl-1-( -n-octadecyl)-3-(4-methylphenyl)urea    122  1-Benzyl-1-(1-naphthylmethyl)-3-(4-methylphenyl)urea    123  1-Benzyl-1-(cyclopentyl)-3-(4-methylphenyl)urea    124  1-Benzyl-1-(4-chlorobenzyl)-3-(4-methylphenyl)urea    125  1-Benzyl-1-(4-methylbenzyl)-3-(4-methylphenyl)urea    126  1-Benzyl-1-( -n-pentyl)-3-(4-chlorophenyl)urea    127  1-Benzyl-1-( -n-heptyl)-3-(4-chlorophenyl)urea    128  1-Benzyl-1-( -n-nonyl)-3-(4-chlorophenyl)urea    129  1-Benzyl-1-( -n-decyl)-3-(4-chlorophenyl)urea    130  1-Benzyl-1-( -n-tridecyl)-3-(4-chlorophenyl)urea    131  1-Benzyl-1-( -n-tetradecyl)-3-(4-chlorophenyl)urea    132  1-Benzyl-1-( -n-hexadecyl)-3-(4-chlorophenyl)urea    133  1-Benzyl-1-(1-naphthylmethyl)-3-(4-chlorophenyl)urea    134  1-Benzyl-1-(cyclohexyl)-3-(4-chlorophenyl)urea    135  1-Benzyl-1-(cyclopentyl)-3-(4-chlorophenyl)urea    136  1-Benzyl-1-(4-chlorobenzyl)-3-(4-chlorophenyl)urea    137  1-Benzyl-1-(3-chlorobenzyl)-3-(4-chlorophenyl)urea    138  1-Benzyl-1-(4-methylbenzyl)-3-(4-chlorophenyl)urea    139  1-Benzyl-1-( -n-hexyl)-3-(3,4-dichlorophenyl)urea    140  1-Benzyl-1-( -n-octyl)-3-(3,4-dichlorophenyl)urea    141  1-Benzyl-1-( -n-undecyl)-3-(3,4-dichlorophenyl)urea    142  1-Benzyl-1-( -n-tetradecyl)-3-(3,4-dichlorophenyl)urea    143  1-Benzyl-1-( -n-octadecyl)-3-(3,4-dichlorophenyl)urea    144  1-Benzyl-1-(cyclohexyl)-3-(3,4-dichlorophenyl)urea    145  1-Benzyl-1-(1-naphthylmethyl)-3-(3,4-dichlorophenyl)urea    146  1-Benzyl-1-(3-chlorobenzyl)-3-(3,4-dichlorophenyl)urea    147  1-Benzyl-1-(4-chlorobenzyl)-3-(3,4-dichlorophenyl)urea    148  1-Benzyl-1-(3-methylbenzyl)-3-(3,4-dichlorophenyl)urea    149  1-Benzyl-1-(4-methylbenzyl)-3-(3,4-dichlorophenyl)urea    150  1-Benzyl-1-( -n-butyl)-3-(3-phenyl)thiourea                                            83-  85    151  1-Benzyl-1-( -n-butyl)-3-(2-methylphenyl)thiourea    152  1-Benzyl-1-( -n-butyl)-3-(3-methylphenyl)thiourea    153  1-Benzyl-1-( -n-butyl)-3-(4-methylphenyl)thiourea    154  1-Benzyl-1-( -n-butyl)-3-(3-ethylphenyl)thiourea    155  1-Benzyl-1-( -n-butyl)-3-(4-ethylphenyl)theourea    156  1-Benzyl-1-( -n-butyl)-3-(4-isopropylphenyl)thiourea    157  1-Benzyl-1-( -n-butyl)-3-(4- -n-butylphenyl)thiourea    158  1-Benzyl-1-( -n-butyl)-3-(2,3-dimethylphenyl)thiourea    159  1-Benzyl-1-( -n-butyl)-3-(2,5-dimethylphenyl)thiourea    160  1-Benzyl-1-( -n-butyl)-3-(2,6-dimethylphenyl)thiourea    161  1-Benzyl-1-( -n-butyl)-3-(3,4-dimethylphenyl)thiourea    162  1-Benzyl-1-( -n-butyl)-3-(3,5-dimethylphenyl)thiourea    163  1-Benzyl-1-( -n-butyl)-3-(2,4,5-trimethylphenyl)thiourea    164  1-Benzyl-1-( -n-butyl)-3-(2,4,6-trimethylphenyl)thiourea    165  1-Benzyl-1-( -n-butyl)-3-(4-methoxyphenyl)thiourea    166  1-Benzyl-1-( -n-butyl)-3-(2,4-dimethoxyphenyl)thiourea    167  1-Benzyl-1-( -n-butyl)-3-(3-methylthiophenyl)thiourea    168  1-Benzyl-1-( -n-butyl)-3-(2-chlorophenyl)thiourea    169  1-Benzyl-1-( -n-butyl)-3-(3-chlorophenyl)thiourea    170  1-Benzyl-1-( -n-butyl)-3-(4-chlorophenyl)thiourea    171  1-Benzyl-1-( -n-butyl)-3-(2-bromophenyl)thiourea    172  1-Benzyl-1-( -n-butyl)-3-(4-bromophenyl)thiourea    173  1-Benzyl-1-( -n-butyl)-3-(4-fluorophenyl)thiourea    174  1-Benzyl-1-( -n-butyl)-3-(4-iodophenyl)thiourea    175  1-Benzyl-1-( -n-butyl)-3-(2,3-dichlorophenyl)thiourea    176  1-Benzyl-1-(  -n-butyl)-3-(2,4-dichlorophenyl)thiourea    177  1-Benzyl-1-( -n-butyl)-3-(2,5-dichlorophenyl)thiourea    178  1-Benzyl-1-( -n-butyl)-3-(3,5-dichlorophenyl)thiourea    179  1-Benzyl-1-( -n-butyl)-3-(2,4,6-trichlorophenyl)thiourea    180  1-Benzyl-1-( -n-butyl)-3-(2,4-difluorophenyl)thiourea    181  1-Benzyl-1-(4-phenyl- -n-butyl)-3-(2,4-dimethylphenyl)thiourea    182  1-Benzyl-1-( -n-hexyl)-3-(2,4-dimethylphenyl)thiourea    183  1-Benzyl-1-( -n-undecyl)-3-(2,4-dimethylphenyl)thiourea    184  1-Benzyl-1-( -n-tetradecyl)-3-(2,4-dimethylphenyl)thiourea    185  1-Benzyl-1-( -n-hexadecyl)-3-(2,4-dimethylphenyl)thiourea    186  1-Benzyl-1-(4-cyclohexyl- -n-butyl)-3-(2,4-dimethylphenyl)thiourea    187  1-Benzyl-1-(cyclopentyl)-3-(2,4-dimethylphenyl)thiourea    188  1-Benzyl-1-(1-naphthylmethyl)-3-(2,4-dimethylphenyl)thiourea    189  1-Benzyl-1-(3-chlorobenzyl)-3-(2,4-dimethylphenyl)thiourea    190  1-Benzyl-1-(4-chlorobenzyl)-3-(2,4-dimethylphenyl)thiourea    191  1-Benzyl-1-[2-(4-chlorophenyl)ethyl]-3-(2,4-dimethylphenyl)thiourea    192  1-Benzyl-1-(2,4-dichlorobenzyl)-3-(2,4-dimethylphenyl)thiourea    193  1-Benzyl-1-(4-methoxybenzyl)-3-(2,4-dimethylphenyl)thiourea    194  1-Benzyl-1-[2-(2-methoxyphenyl)ethyl]-3-(2,4-dimethylphenyl)thiourea    195  1-Benzyl-1-(4-methylbenzyl)-3-(2,4-dimethylphenyl)thiourea    196  1-Benzyl-1-(3-methylbenzyl)-3-(2,4-dimethylphenyl)thiourea    197  1-Benzyl-1-[2-(4-methylphenyl)ethyl]-3-(2,4-dimethylphenyl)thiourea    198  1-Benzyl-1-(2-phenylethyl)-3-(3-chloro-4-methylphenyl)thiourea    199  1-Benzyl-1-(4-phenyl- -n-butyl)-3-(3-chloro-4-methylphenyl)thiourea    200  1-Benzyl-1-( -n-heptyl)-3-(3-chloro-4-methylphenyl)thiourea    201  1-Benzyl-1-( -n-octyl)-3-(3-chloro-4-methylphenyl)thiourea    202  1-Benzyl-1-(   -n-butyl)-3-(3-chloro-2-methoxyphenyl)urea                                            52-54    203  1-Benzyl-1-( -n-butyl)-3-(5-chloro-2-methoxyphenyl)urea                                            161-163    204  1-( -n-Butyl)-1-(2-fluorobenzyl)-3-(2,4-dimethylphenyl)urea                                            76-77    205  1-( -n-Butyl)-1-(4-fluorobenzyl)-3-(2,4-dimethylphenyl)urea                                            78-79    206  1-( -n-Butyl)-1-(2-chlorobenzyl)-3-(2,4-dimethylphenyl)urea                                            101-102    207  1-( -n-Butyl)-1-(2,6-dichlorobenzyl)-3-(2,4-dimethylphenyl)urea                                            145-146    208  1-(4-Bromobenzyl)-1-( n-butyl)-3-(2,4-dimethylphenyl)urea                                            61-63    209  1-( -n-Butyl)-1-(4- -n-butylbenzyl)-3-(2,4-dimethylphenyl)urea                                            60-62    210  1-(n-Butyl)-1-(4-methylbenzyl)-3-(2,4-dimethylphenyl)urea                                            oil    211  1-(n-Butyl)-1-(4-tert-butylbenzyl)-3-(2,4-dimethylphenyl)urea                                            28-31    212  1-(n-Butyl)-1-(4-chlorobenzyl)-3-(2,4-dimethylphenyl)urea                                            oil    213  1-(n-Butyl)-1-(4-methoxybenzyl)-3-(2,4-dimethylphenyl)urea                                            oil    214  1-(n-Butyl)-1-(3,4-methylenedioxybenzyl)-3-(2,4-dimethylphenyl)urea                                            oil    215  1-(n-Butyl)-1-(4-trifluoromethylbenzyl)-3-(2,4-dimethylphenyl)urea                                            oil    216  1-(n-Butyl)-1-(4-phenylbenzyl)-3-(2,4-dimethylphenyl)urea                                            82-83    217  1-(n-Butyl)-1-(2-phenylethyl)-3-(2,4-dimethylphenyl)urea                                            oil    218  1-(n-Butyl)-1-[2-(4-fluorophenyl)ethyl]-3-(2,4-dimethylphenyl)urea                                            oil    219  1-(n-Butyl)-1-[2-(4-chlorophenyl)ethyl]-3-(2,4-dimethylphenyl)urea                                            oil    220  1-(n-Butyl)-1-[2-(3-methoxyphenyl)ethyl]-3-(2,4-dimethylphenyl)urea                                            oil    221  1-(n-Butyl)-1-(3-phenylpropyl)-3-(2,4-dimethylphenyl)urea                                            oil    222  1-(n-Butyl)-1-[4-(n-pentyl)benzyl]-3-(2,4-dimethylphenyl)urea                                            65-67    223  1-(n-Butyl)-1-[4-(n-hexyl)benzyl]-3-(2,4-dimethylphenyl)urea                                            oil    224  1-(n-Butyl)-1-(3-chlorobenzyl)-3-(2,4-dimethylphenyl)urea                                            oil    225  1-(n-Butyl)-1-[4-(n-butoxy)benzyl]-3-(2,4-dimethylphenyl)urea                                            oil    226  1-(n-Butyl)-1-[  4-(n-pentyloxy)benzyl]-3-(2,4-dimethylphenyl)urea                                            oil    227  1-(n-Butyl)-1-[4-(n-hexyloxy)benzyl]-3-(2,4-dimethylphenyl)urea                                            oil    228  1-(n-Butyl)-1-[4-(n-heptyloxy)benzyl]-3-(2,4-dimethylphenyl)urea                                            oil    229  1-(n-Butyl)-1-(4-nitrobenzyl)-3-(2,4-dimethylphenyl)urea                                            oil    230  1-(n-Butyl)-1-[2-(2-methylphenyl)ethyl]-3-(2,4-dimethylphenyl)urea                                            102-103    231  1-(n-Butyl)-1-[2-(3-methylphenyl)ethyl]-3-(2,4-dimethylphenyl)urea                                            oil    232  1-(n-Butyl)-1-[2-(4-methylphenyl)ethyl]-3-(2,4-dimethylphenyl)urea                                            oil    233  1-(n-Butyl)-1-[2-(4-ethoxyphenyl)ethyl]-3-(2,4-dimethylphenyl)urea                                            oil    234  1-(n-Butyl)-1-[2-(3-fluorophenyl)ethyl]-3-(2,4-dimethylphenyl)urea                                            oil    235  1-(n-Butyl)-1-[2-(2-chlorophenyl)ethyl]-3-(2,4-dimethylphenyl)urea                                            oil    236  1-(n-Butyl)-1-[2-(3-chlorophenyl)ethyl]-3-(2,4-dimethylphenyl)urea                                            oil    237  1-(n-Butyl)-1-[2-(4-bromophenyl)ethyl]-3-(2,4-dimethylphenyl)urea                                            oil    238  1-(n-Butyl)-1-[2-(3,4-dimethoxyphenyl)ethyl-3-(2,4-dimethyl-                                            oil         phenyl)urea    239  1-(n-Butyl)-1-(2-adamantylethyl)-3-(2,4-dimethylphenyl)urea                                            134-135    240  1-(n-Butyl)-1-(3-cyclohexyl-2-phenylethyl)-3-(2,4-dimethylphenyl)urea         1                                  112-113    241  1-(n-Butyl)-1-(di-(4-chlorophenyl)ethyl)-3-(2,4-dimethylphenyl)urea                                            145-147    242  1-(n-Butyl)-1-(2,4-dichlorobenzyl)-3-(2,4-dimethylphenyl)urea                                            120-121    243  1-(n-Butyl)-1-(3-trifluoromethylbenzyl)-1-(4-fluorobenzyl)-3-(2,4-di-         3                                  114-115         methylphenyl)urea    244  1-(4-Chlorobenzyl)-1-(1-naphthylmethyl-3-(2,4-dimethylphenyl)urea                                            134-136    245  1-(4-Methoxybenzyl)-1-(2,4-dichlorobenzyl)-3-(2,4-dimethylphenyl)urea         .                                  124 126    246  1-(3-Chlorobenzyl)-1-(4-methoxybenzyl)-3-(2,4-dimethylphenyl)urea                                            108-109    247  1-(4-Phenylbenzyl)-1-(3,4-dichlorobenzyl)-3-(2,4-dimethylphenyl)urea                                            103-105    248  1-(2-Fluorobenzyl)-1-(4-methylbenzyl)-3-(2,4-dimethylphenyl)urea                                            128-130    249  1-(4-Chlorobenzyl)-1(3,4-dimethoxybenzyl)-3-(2,4-dimethylphenyl)urea                                            94-96    250  1-(4-Fluorobenzyl)-1-(3,4-methylenedioxybenzyl)-3-(2,4-dimethyl-                                            122-124         phenyl)urea    251  1-(n-Butyl)-1-(4-methylthiobenzyl)-3-(2,4-dimethylphenyl)urea                                            oil    252  1-(2,4-Dichlorobenzyl)-1-(4-methylthiobenzyl)-3-(2,4-dimethyl-                                            124-125         phenyl)urea    253  1-[2-(3,4-Dimethoxyphenyl)ethyl]-1-(3,4-methylenedioxybenzyl)-3-(2,4-                                            oil         dimethylphenyl)urea    254  1-[2-(2-Methylphenyl)ethyl]-1-(2,4-dichlorobenzyl)-3-(2,4-dimethyl-                                            120-122         phenyl)urea    255  1-[2-(4-Methylphenyl)ethyl]-1-(4-chlorobenzyl)-3-(2,4-dimethyl-                                            oil         phenyl)urea    256  1-[2-(4-Ethoxyphenyl)ethyl]-1-(2-chlorobenzyl)-3-(2,4-dimethyl-                                            oil         phenyl)urea    257  1-[2-(3-Fluorophenyl)ethyl]-1-(3-methoxybenzyl)-3-(2,4-dimethyl-                                            94-95         phenyl)urea    258  1-[2-(3-Methoxyphenyl)ethyl]-1-(3-chlorobenzyl)-3-(2,4-dimethyl-                                            73-74         phenyl)urea    259  1-(3,3-Diphenylpropyl)-1-(4-fluorobenzyl)-3-(2,4-dimethylphenyl)urea                                            109-110    260  1-(n-Butyl)-1-(3,3-diphenylpropyl)-3-(2,4-dimethylphenyl)urea                                            94-95    261  1-(n-Butyl)-1-(4-cyclohexylbutyl)-3-(2,4-dimethylphenyl)urea                                            oil    262  1-[2-(3,4-Dimethoxyphenyl)ethyl]-1-(3-chloro-4-methylbenzyl)-3-                                            gum         (2,4-dimethylphenyl)urea    263  1-[2-(2-Methylphenyl)ethyl]-1-(4-bromobenzyl)-3-(2,4-dimethyl-                                            126-127         phenyl)urea    264  1-[2-(3-Trifluoromethylphenyl)ethyl]-1-(2-chlorobenzyl)-3-(2,4-                                            115-117         dimethylphenyl)urea    265  1-(2-Fluorobenzyl)-1-(2-methoxybenzyl)-3-(2,4-dimethylphenyl)urea                                             96-98    266  1-[2-(3,4-Dimethoxyphenyl)ethyl]-1-(4-fluorobenzyl)-3-(2,4-dimethyl-                                            gum         phenyl)urea    267  1-[2-(4-Ethoxyphenyl)ethyl]-1-(2,4-dimethylbenzyl)-3-(2,4-dimethyl-                                            gum         phenyl)urea    268  1-[2-(3-Methylphenyl)ethyl]-1-(3-nitrobenzyl)-3-(2,4-dimethyl-                                            99-101         phenyl)urea    269  1-[2-(2,5-Dimethoxyphenyl)ethyl]-1-(3-chlorobenzyl)-3-(2,4-dimethyl-                                            86-88         phenyl)urea    270  1-(n-Butyl)-1-(2-methyl-2,2-diphenyl)ethyl-3-(2,4-dimethylphenyl)urea                                            159-160    271  1-(n-Butyl)-1-(4-hexyloxybenzyl)-3-(2,4,6-trimethylphenyl)urea                                            90-91    272  1-(n-Butyl)-1-(4-heptyloxybenzyl)-3-(2,4,6-trimethylphenyl)urea                                            86-87    273  1-(n-Butyl)-1-benzyl-3-(4-trifluoroacetylamino-3,5-dichloro-                                            173-175         phenyl)urea    274  1-Benzyl-1-(4-n-butylbenzyl)-3-(2,4-dimethylphenyl)urea                                            oil    275  1-Benzyl-1-(4-n-butylbenzyl)-3-(2,4,6-trimethylphenyl)urea                                            oil    276  1-Benzyl-1-(4-n-butylbenzyl)-3-(4-n-butylphenyl)urea                                            yellow oil    277  1-Benzyl-1-(4-n-butylbenzyl)-3-(4-phenoxyphenyl)urea                                            79-80    278  1-(n-Heptyl)-1-(4-n-butylbenzyl)-3-(2,4-dimethylphenyl)urea                                            yellow oil    279  1-(n-Heptyl)-1-(4-n-butylbenzyl)-3-(2,4,5-trimethylphenyl)urea                                            yellow oil    280  1-Benzyl-1-[2-phenyl-1-(4-benzyloxyphenyl)ethyl]-3-(2,4,5-trimethyl-                                            157-158         phenyl)urea    281  1-(n-Heptyl)-1-(4-butyloxybenzyl)-3-(2,4-dimethylphenyl)urea                                            oil    282  1-(n-Heptyl)-1-(4-butyloxybenzyl)-3-(2,4,5-trimethylphenyl)urea                                            yellow oil    283  1-Benzyl-1-(4-butyloxybenzyl)-3-(2,4-dimethylphenyl)urea                                            solid    284  1-Benzyl-1-(4-butyloxybenzyl)-3-(2,4,5-trimethlphenyl)urea                                            solid    285  1-Benzyl-1-(4-n-butylbenzyl)-3-(2,4,5-trimethylphenyl)urea                                            yellow oil    286  1-Benzyl-1-[2-phenyl-1-(4-benzyloxyphenyl)ethyl]-3-(2,4,6-trimethyl-                                            140-141         phenyl)urea    287  1-(n-Heptyl)-1-(4-n-butoxybenzyl)-3-(2,4,6-trichlorophenyl)urea                                            63-64    288  1-(n-Heptyl)-(4-n-butoxybenzyl)-3-(2,4-dichlorophenyl)urea                                            gum    289  1-(n-Heptyl)-(4-n-butoxybenzyl)-3-(2-trifluoromethyl-4-chloro-                                            gum         phenyl)urea    290  1-Benzyl-1-(4-n-butoxybenzyl)-3-(2,4,6-trichlorophenyl)urea                                            91-93    291  1-Benzyl-1-(4-n-butoxybenzyl)-3-(2,4-dichlorophenyl)urea                                            gum    292  1-Benzyl-1-(4-n-butoxybenzyl)-3-(2-trifluoromethyl-4-chloro-                                            gum         phenyl)urea    293  1-(n-Heptyl)-1-(4-n-butoxybenzyl)-3-(3-trifluoromethylphenyl)urea                                            gum    294  1-(n-Benzyl)-1-(4-n-butoxybenzyl)-3-(3-trifluoromethylphenyl)urea                                            gum    295  1-(n-Heptyl)-1-(4-n-butylbenzyl)-3-(2,4-dichlorophenyl)urea                                            gum    296  1-(n-Heptyl)-1-(4-n-butylbenzyl)-3-(2-trifluoromethyl-4-chloro-                                            gum         phenyl)urea    297  1-(n-Heptyl)-1-(4-n-butylbenzyl)-3-(2,4,6-trichlorophenyl)urea                                            gum    298  1-(n-Heptyl)-1-(4-n-butylbenzyl)-3-(3-trifluoromethylphenyl)urea                                            gum    299  1-(n-Heptyl)-1-(4-n-butylbenzyl)-3-(2,4,5-trichlorophenyl)urea                                            gum    300  1-Benzyl-1-(4-n-butoxybenzyl)-3-(2-methyl-4-chlorophenyl)urea                                            107-108    301  1-(n-Heptyl)-1-(4-n-butoxybenzyl)-3-(2,4-difluorophenyl)urea                                            gum    302  1-(n-Heptyl)-1-(4-n-butoxybenzyl)-3-(2-methyl-4-chlorophenyl)urea                                            gum    303  1-(n-Heptyl)-1-(2-furyl)-3-(2,4,5-trimethylphenyl)urea                                            65-67    304  1-(n-Heptyl)-1-(2-furyl)-3-(2,4,6-trichlorophenyl)urea                                            yellow oil    305  1-(n-Heptyl)-1-(4-n-butylbenzyl)-3-(2-methyl-4-chlorophenyl)urea                                            oil    306  1-(n-Heptyl)-1-(4-n-butylbenzyl)-3-(4-carboethoxyphenyl)urea                                            65-66    307  1-(n-Heptyl)-1-(4-n-butylbenzyl)-3-(2-methylphenyl)urea                                            oil    308  1-(n-Heptyl)-1-(4-n-butylbenzyl)-3-(3-methylphenyl)urea                                            oil    309  1-(n-Heptyl)-1-(4-n-butylbenzyl)-3-(4-carboxyphenyl)urea                                            147-149    310  1-(n-Heptyl)-1-(2-phenylethyl)-3-(2-methyl-4-chlorophenyl)urea                                            gum    311  1-(n-Heptyl)-1-(2-phenylethyl)-3-(2,4,5-trichlorophenyl)urea                                            gum    312  1-(n-Heptyl)-1-(2-phenylethyl)-3-(2-trifluoromethyl-4-chloro-                                            gum         phenyl)urea    313  1-(n-Heptyl)-1-(2-phenylethyl)-3-(2,4-dimethylphenyl)urea                                            gum    314  1-(n-Heptyl)-1-(2-phenylethyl)-3-(2,4-dichlorophenyl)urea                                            gum    315  1-(n-Heptyl)-1-(2-phenylethyl)-3-(2,4-difluorophenyl)urea                                            gum    316  1-(n-Heptyl)-1-(2-phenylethyl)-3-(3-trifluoromethylphenyl)urea                                            gum    317  1-Benzyl-1-[2-phenyl-1-(4-benzyloxyphenyl)ethyl]-3-(2,4,6-tri-                                            131-133         chlorophenyl)urea    318  1-(4-n-Pentylbenzyl)-1-(4-n-pentyloxybenzyl)-3-(2,4,6-trichloro-                                            oil         phenyl)urea    319  1-(4-n-Pentylbenzyl)-1-(4-n-pentyloxybenzyl)-3-(2,4-dichloro-                                            oil         phenyl)urea    320  1-(4-n-Pentylbenzyl)-1-(4-n-pentyloxybenzyl)-3-(2,4,5-trichloro-                                            oil         phenyl)urea    321  1-(4-n-Pentylbenzyl)-1-(4-n-pentyloxybenzyl)-3-(2-trifluoromethyl-                                            oil         4-chlorophenyl)urea    322  1-(4-n-Pentylbenzyl)-1-(4-n-pentyloxybenzyl)-3-(3-trifluoromethyl-                                            oil         phenyl)urea    323  1-(4-n-Pentylbenzyl)-1-(4-n-pentyloxybenzyl)-3-(2,4-difluoro-                                            oil         phenyl)urea    324  1-(4-n-Pentylbenzyl)-1-(4-n-pentyloxybenzyl)-3-(2-methyl-4-chloro-                                            oil         phenyl)urea    325  1-(4-Chlorobenzyl)-1-(1-naphthylmethyl)-3-(2,4,6-trichlorophenyl)urea                                            157-159    326  1-(4-Chlorobenzyl)-1-(1-naphthylmethyl)-3-(2-methyl-4-chloro                                            168-169         phenyl)urea    327  1-(4-Chlorobenzyl)-1-(1-naphthylmethyl)-3-(2,4-difluorophenyl)urea                                            122-124    328  1-(4-Chlorobenzyl)-1-(1-naphthylmethyl)-3-(3-trifluoromethyl-                                            127-129         phenyl)urea    329  1-(4-Chlorobenzyl)-1-(1-naphthylmethyl)-3-(2,4,5-trichlorophenyl)urea                                            110-113    330  1-Benzyl-1-[2-phenyl-1-(4-benzyloxyphenyl)ethyl]-3-(2,4,5-trichloro-                                            142-145         phenyl)urea    331  1-Benzyl-1-(4-n-butyloxybenzyl)-3-(2,4,5-trichlorophenyl)urea                                            oil    332  1-Benzyl-1-[2-phenyl-1-(4-benzyloxyphenyl)ethyl]-3-(2,4-difluoro-                                            84-85         phenyl)urea    333  1-Benzyl-1-(4-n-butoxybenzyl)-3-(2,4-difluorophenyl)urea                                            oil    334  1-Benzyl-1-[2-phenyl-1-(4-benzyloxyphenyl)ethyl]-3-(2,4-dichloro-                                            126-128         phenyl)urea    335  1-Benzyl-1-[2-phenyl-1-(4-benzyloxyphenyl)ethyl]-3-(2-trifluoro-                                             99-101         methyl-4-chlorophenyl)urea    336  1-Benzyl-1-[2-phenyl-1-(4-benzyloxyphenyl)ethyl]-3-(3-trifluoro-                                            102-104         methylphenyl)urea    337  1-Benzyl-1-[2-phenyl-1-(4-benzyloxyphenyl)ethyl]-3-(2-methyl-4-                                            125-126         chlorophenyl)urea    338  1-(4-Chlorobenzyl)-1-(1-naphthylmethyl)-3-(2,4-dichlorophenyl)urea                                            96-98    339  1-(4-Chlorobenzyl)-1-(1-naphthylmethyl)-3-(2-trifluoromethyl-4-                                            yellow glass         chlorophenyl)urea    340  1-[2-(4-Methylphenyl)ethyl]-1-(3-chlorobenzyl)-3-(2,4-dimethyl-                                            34-35         phenyl)urea    341  1-(n-Butyl)-1-benzyl-3-(3-chloro-2-hydroxyphenyl)urea                                            59-62    342  1-[2-(3-Fluorophenyl)ethyl]-1-(4-methylbenzyl)-3-(2,4-dimethyl-                                            74-75         phenyl)urea    343  1-(n-Butyl)-1-benzyl-3-(2-nitrophenyl)urea                                            yellow oil    344  1-(3,4-Methylenedioxyphenyl)-1-(3,3-diphenylpropyl)-3-(2,4-                                            135-137         dimethylphenyl)urea    345  1-(n-Butyl)-1-[3-(3,4-dimethoxyphenyl)propyl]-3-(2,4-dimethyl-                                            yellow oil         phenyl)urea    346  1-(3,4-Dimethylbenzyl)-1-(2-chlorobenzyl)-3-(2,4-dimethylphenyl)urea                                            113-115    347  1-(n-Butyl)-1-benzyl-3-(2-hydroxy-5-chlorophenyl)urea                                            113-115    348  1-(3,4-Dimethoxybenzyl)-1-[2-(4-methylphenyl)ethyl]-3-(2,4-di-                                            gum         methylphenyl)urea    349  1-(n-Butyl)-1-benzyl-3-(4-amino-3,5-dichlorophenyl)urea                                            121-124    350  1-(n-Butyl)-1-(benzyl)-3-[4-(chloroacetamido)-3,5-dichloro-                                            135-138         phenyl)urea    351  1-[2-(2-Chlorophenyl)ethyl]-1-(3,4-dimethylbenzyl)-3-(2,4-dimethyl-                                            96-98         phenyl)urea    352  1-[2-(2-Chlorophenyl)ethyl]-1-(3-methylbenzyl)-3-(2,4-dimethyl-                                            92-95         phenyl)urea    353  1-(n-Butyl)-1-benzyl-3-(4-chloro-2-methylphenyl)urea                                            83-84    354  1-(3,3-Dimethylbutyl)-1-[4-(n-butyl)benzyl]-3-(4-chloro-2-methyl-                                            88-91         phenyl)urea    355  1-(3,3-Dimethylbutyl)-1-[4-(n-butoxy)benzyl]-3-(4-chloro-2-methyl-                                            106-107         phenyl)urea    356  1-(3,3-Dimethylbutyl)-1-[4-(n-butoxy)benzyl]-3-(2,4,6-trichloro-                                            114-115         phenyl)urea    357  1-(3,3-Dimethylbutyl)-1-[4-(n-butoxy)benzyl]-3-(2,4-difluoro-                                            oil         phenyl)urea    358  1-(3,3-Dimethylbutyl)-1-[4-(n-butyl)benzyl]-3-(2,4-difluoro-                                            oil         phenyl)urea    359  1-(3,3-Dimethylbutyl)-1-[4-(n-butyl)benzyl]-3-(2,4,6-trichloro-                                            solid         phenyl)urea    360  1-(5,5-Dimethylhexyl)-1-[4-(n-butyl)benzyl]-3-(4-chloro-2-methyl-                                            oil         phenyl)urea    361  1-(5,5-Dimethylhexyl)-1-[4-(n-butyl)benzyl]-3-(2,4-difluoro-                                            oil         phenyl)urea    362  1-(5,5-Dimethylhexyl)-1-[4-(n-butyl)benzyl]-3-(2,4,6-trichloro-                                            oil         phenyl)urea    363  1-(3,3-Dimethylbutyl)-1-(4-chlorobenzyl)-3-(4-chloro-2-methyl-                                            110-111         phenyl)urea    364  1-(3,3-Dimethylbutyl)-1-benzyl-3-(2,4-difluorophenyl)urea                                            82-84    365  1-(3,3-Dimethylbutyl)-1-(4-chlorobenzyl)-3-(2,4-difluorophenyl)urea                                            67-70    366  1-(3,3-Dimethylbutyl)-1-(4-chlorobenzyl)-3-(2,4,6-trichloro-                                            148-149         phenyl)urea    367  1-(n-Heptyl)-1-[4-(n-butyl)benzyl]-3-(4-trifluoromethylphenyl)urea                                            69-71    368  1-(3,3-Dimethylbutyl)-1-[4-butyl)benzyl]-3-(4-trifluoromethyl-                                            103-104         phenyl)urea    369  1-(3,3-Dimethylbutyl)-1-(4-chlorobenzyl)-3-(4-trifluoromethyl-                                            140-141         phenyl)urea    370  1-(3,3-Dimethylbutyl)-1-[4-(2,2-dimethylpropyl)benzyl]-3-(2,4-                                            oil         difluorophenyl)urea    371  1-(3,3-Dimethylbutyl)-1-[4-(2,2-dimethylpropyl)benzyl]-3-(4-chloro-                                            125-130         2-methylphenyl)urea    372  1-(3,3-Dimethylbutyl)-1-[4-(2,2-dimethylpropyl)benzyl]-3-(2,4,6-                                            glass         trichlorophenyl)urea    373  1-(3,3-Dimethylbutyl)-1-[4-(n-butyl)benzyl]-3-(4-chloro-2,6-                                            138-139         dimethylphenyl)urea    374  1-(3,3-Dimethylbutyl)-1-(4-chlorobenzyl)-3-(4-chloro-2,6-dimethyl-                                            178-180         phenyl)urea    375  1-(n-Heptyl)-1-[4-(n-butyl)benzyl]-3-(4-chloro-2,6-dimethyl-                                            48-50         phenyl)urea    376  1-(3,3-Dimethylbutyl)-1-[4-(2,2-dimethylpropyl)benzyl]-3-(4-chloro-                                            148-150         2,6-dimethylphenyl)urea    377  1-(3,3-Dimethylbutyl)-1-benzyl-3-(4-chloro-2-methylphenyl)urea                                            114-115    378  1-(n-Heptyl)-1-[4-(n-butyl)benzyl]-3-(4-chloro-2,5-dimethyl-                                            oil         phenyl)urea    379  1-(3,3-Dimethylbutyl)-1-(benzyl)-3-(4-chloro-2,5-dimethylphenyl)urea                                            solid    380  1-(3,3-Dimethylbutyl)-1-[4-(n-butyl)benzyl]-3-(4-chloro-2,5-dimethyl-                                            102-103         phenyl)urea    381  1-(3,3-Dimethylbutyl)-1-[4-(2,2-dimethylpropyl)benzyl]-3-(4-chloro-                                            160-161         2,5-dimethylphenyl)urea    382  1-[(4-butylphenyl)methyl]-1-[3,3-dimethylbutyl]-3-[2,4,6-trifluoro-                                            oil         phenyl]urea    383  1-[(4-butylphenyl)methyl]-1-(n-heptyl)-3-[2,4,6-trifluorophenyl]urea                                            35-36    384  1-[(4-butoxyphenyl)methyl]-1-[3,3-dimethylbutyl]-3-[2,4,6-trifluoro-         phenyl]urea    385  1-[(4-butoxyphenyl)methyl]-1-(n-heptyl)-3-[2,4,6-trifluorophenyl]urea    386  1-Benzyl-1-[3,3-dimethylbutyl]-3-[2,4,6-trifluorophenyl]urea                                            108-110    387  1-Benzyl-1-(n-heptyl)-3-[2,4,6-trifluorophenyl]urea    388  1-[3,3-dimethylbutyl]-1-[[4-(2,2-dimethylpropyl)phenyl]methyl]-3-                                            39-40         [2,4,6-trifluorophenyl]urea    389  1-[(4-chlorophenyl)methyl]-1-[3,3-dimethylbutyl]-3-[2,4,6-trifluoro-         phenyl]urea    390  1-(n-Heptyl)-1-[4-(2,2-dimethylpropyl)phenylmethyl]-3-(2,4-difluoro-                                            40-46         phenyl)urea    391  1-(n-Heptyl)-1-[4-(2,2-dimethylpropyl)phenylmethyl]-3-(4-chloro-2,6-                                            111-113         dimethylphenyl)urea    392  1-(n-Heptyl)-1-[4-(2,2-dimethylpropyl)phenylmethyl]-3-(2,4,6-tri-                                            oil         fluorophenyl)urea    393  1-(n-Heptyl)-1-(4-isobutylphenylmethyl)-3-(2,4-difluorophenyl)urea    394  1-(n-Heptyl)-1-(4-isobutylphenylmethyl)-3-(4-chloro-2,6-dimethyl-                                            87-88         phenyl)urea    395  1-(n-Heptyl)-1-(4-isobutylphenylmethyl)-3-(2,4,6-trifluorophenyl)urea                                            73-74    396  1-(n-Heptyl)-1-(4-isopentylphenylmethyl)-3-(2,4-difluorophenyl)urea                                            oil    397  1-(n-Heptyl)-1-(4-isopentylphenylmethyl)-3-(4-chloro-2,6-dimethyl-                                            oil         phenyl)urea    398  1-(n-Heptyl)-1-(4-isopentylphenylmethyl)-3-(2,4,6-trifluorophe-                                            oil         nyl)urea    399  1-(6-Hydroxyheptyl)-1-[4-(2,2-dimethylpropyl)benzyl]-3-(4-chloro-2,6-                                            oil         dimethylpyhenyl)urea    400  1-(Isopentyl)-1-[4-(isopropyl)benzyl]-3-(2,4-difluorophenyl)urea                                            oil    401  1-(Isopentyl)-1-[4-(isopropyl)benzyl]-3-(4-chloro-2,6-dimethyl-                                            115-117         phenyl)urea    402  1-(Isopentyl)-1-[4-(isopropyl)benzyl]-3-(2,4,6-trifluorophenyl)urea                                            oil    403  1-(6-Hydroxyheptyl)-1-[4-(2,2-dimethylpropyl)benzyl]-3-(2,4-di-                                            oil         fluorophenyl)urea    404  1-(n-Heptyl)-1-[4-(isobutyl)benzyl]-3-(4-chloro-2-methylphenyl)urea                                            oil    405  1-(n-Heptyl)-1-[4-(isopropyl)benzyl]-3-(2,4-difluorophenyl)urea                                            oil    406  1-(n-Heptyl)-1-[  4-(isopropyl)benzyl]-3-(4-chloro-2,6-dimethyl-                                            121-123         phenyl)urea    407  1-(n-Heptyl)-1-[4-(isopropyl)benzyl]-3-(4-chloro-2-methylphenyl)urea                                            oil    408  1-(n-Heptyl)-1-[4-(isopropyl)benzyl]-3-(2,4,6-trifluorophenyl)urea                                            60-61    409  1-(n-Heptyl)-1-[4-(4-isopentyl)benzyl]-3-(4-chloro-2-methylphenyl)-                                            oil         urea    410  1-(n-Heptyl)-1-[4-(isopentyl)benzyl]-3-(4-chloro-2,6-dimethyl-                                            48-52         phenyl)urea    411  1-(n-Heptyl)-1-[4-(2-acetoxyethyl)benzyl]-3-(2,4-difluorophenyl)urea                                            oil    412  1-(n-Heptyl)-1-[4-(2-hydroxyethyl)benzyl]-3-(2,4-difluorophenyl)urea                                            oil    413  1-(n-Heptyl)-1-[4-carbomethoxymethyl)benzyl]-3-(2,4-difluorophenyl)-                                            oil         urea    414  1-(n-Heptyl)-1-[4-(carboxymethyl)benzyl]-3-(2,4-difluorophenyl)urea                                            solid    415  1-(n-Heptyl)-1-[4-(4-hydroxybutyl)benzyl]-3-(4-chloro-2,6-dimethyl-                                            65-66         phenyl)urea    416  1-(n-Heptyl)-1-[4-(3-carboxypropyl)benzyl]-3-(4-chloro-2,6-dimethyl-                                            oil         phenyl)urea    417  1-(n-Heptyl)-1-[4-(4-chlorobutyl)benzyl]-3-(4-chloro-2,6-dimethyl-                                            oil         phenyl)urea    418  1-(n-Heptyl)-1-[4-(3-carboethoxypropyl)benzyl]-3-(4-chloro-2,6-                                            oil         dimethylphenyl)urea    419  1-(n-Heptyl)-1-[4-(3-methylbutoxy)benzyl]-3-(2,4-difluorophenyl)urea                                            oil    420  1-(n-Heptyl)-1-[4-(4-ethylthiobutyl)benzyl]-3-(4-chloro-2,6-dimethyl-                                            47-52         phenyl)urea    421  1-(n-Heptyl)-1-[4-(4-isopropylthiobutyl)benzyl]-3-(4-chloro-2,6-                                            40-44         dimethylphenyl)urea    422  1-(Isoheptyl)-1-[4-(isopentyl)benzyl]-3-(2,4-difluorophenyl)urea                                            oil    423  1-(Isoheptyl)-1-[4-(isopentyl)benzyl]-3-(4-chloro-2,6-dimethyl-                                            84-86         phenyl)urea    424  1-(Isoheptyl)-1-[4-(isopentyl)benzyl]-3-(2,4,6-trifluorophenyl)urea                                            oil    425  1-(n-Heptyl)-1-[4-(4-isopropylthiobutyl)benzyl]-3-(2,4-difluoro-                                            oil         phenyl)urea    426  1-(n-Heptyl)-1-[4-(isohexyloxy)benzyl]-3-(2,4-difluorophenyl)urea                                            oil    427  1-(n-Heptyl)-1-[4-(2-ethylhexyl)benzyl] -3-(2,4,6-trifluorophenyl)ure         a                                  oil    428  1-(n-Heptyl)-1-[4-(2-ethylhexyl)benzyl]-3-(4-chloro-2,6-dimethyl-                                            oil         phenyl)urea    429  1-(n-Heptyl)-1-[4-(2-ethylbutyl)benzyl]-3-(2,4-difluorophenyl)urea                                            oil    430  1-(n-Heptyl)-1-[4-(2-ethylbutyl)benzyl)-3-(2,4,6-trifluorophenyl)urea                                            oil    431  1-(n-Heptyl)-1-[4-(isohexyl)benzyl]-3-(2,4-difluorophenyl)urea                                            oil    432  1-(n-Heptyl)-1-[4-(isohexyl)benzyl]-3-(4-chloro-2,6-dimethylphenyl)-                                            56-61         urea    433  1-(n-Heptyl)-1-[4-(isohexyl)benzyl]-3-(2,4,6-trifluorophenyl)urea                                            oil    434  1-(n-Heptyl)-1-[4-(cyclopentyl)benzyl]-3-(2,4-difluorophenyl)urea                                            oil    435  1-(n-Heptyl)-1-[4-(cyclopentyl)benzyl]-3-(4-chloro-2,6-dichloro-                                            119-121         phenyl)urea    436  1-(n-Heptyl)-1-[4-(2-ethylhexyl)benzyl]-3-(2,4-difluorophenyl)urea                                            oil    437  1-(n-Heptyl)-1-[4-(cyclopentyl)benzyl]-3-(2,4,6-trifluorophenyl)urea                                            solid    438  1-(n-Heptyl)-1-[4-(2-ethylbutyl)benzyl]-3-(4-chloro-2,6-dimethyl-                                            oil         phenyl)urea    439  1-(n-Heptyl)-1-[4-(2-methylpentyl)benzyl]-3-(2,4-difluorophenyl)urea                                            oil    440  1-(n-Heptyl)-1-[4-(2-methylpentyl)benzyl]-3-(2,4,6-trifluorophenyl)-                                            oil         urea    441  1-(n-Heptyl)-1-[4-(2-methylpentyl)benzyl]-3-(4-chloro-2,6-dimethyl-                                            oil         phenyl)urea    442  1-(n-Heptyl)-1-[4-(3-methylpentyl)benzyl]-3-(2,4-difluorophenyl)urea                                            oil    443  1-(n-Heptyl)-1-[4-(3-methylpentyl)benzyl]-3-(2,4,6-trifluorophenyl)-                                            oil         urea    444  1-(n-Heptyl)-1-[4-(3-methylpentyl)benzyl]-3-(4-chloro-2,6-dimethyl-                                            oil         phenyl)urea    445  1-(n-Heptyl)-1-[4-(cyclobutylmethyl)benzyl]-3-(4-chloro-2,6-dimethyl-                                            solid         phenyl)urea    446  1-(n-Heptyl)-1-[4-(cyclobutylmethyl)benzyl]-3-(2,4-difluorophenyl)-                                            oil         urea    447  1-(n-Heptyl)-1-[4-(cyclopentylmethyl)benzyl]-3-(2,4,6-trifluoro-                                            solid         phenyl)urea    448  1-(n-Heptyl)-1-[4-(4-cyclopentylmethyl)benzyl]-3-(2,4-difluoro-                                            oil         phenyl)urea    449  1-(n-Heptyl)-1-[4-(cyclobutylmethyl)benzyl)]  -3-(2,4,6-trifluoro-                                            solid         phenyl)urea    450  1-(n-Heptyl)-1-[4-(1,5-dimethylhexyl)benzyl]-3-(2,4-difluorophenyl)-                                            oil         urea    451  1-(n-Heptyl)-1-[4-(1,5-dimethylhexyl)benzyl]-3-(4-chloro-2,6-                                            oil         dimethylphenyl)urea    452  1-(n-Heptyl)-1-[4-(1,5-dimethylhexyl)benzyl]-3-(2,4,6-trifluoro-                                            oil         methylphenyl)urea    453  1-(n-Heptyl)-1-[4-(cyclopentylmethyl)benzyl]-3-(4-chloro-2,6-                                            109-111         dimethylphenyl)urea    454  1-(n-Heptyl)-1-[4-(hydroxymethyl)benzyl]-3-(2,4-difluorophenyl)urea                                            oil    455  1-(n-Heptyl)-1-[4-(acetoxymethyl)benzyl]-3-(2,4-difluorophenyl)urea                                            65-71    456  1-(n-Heptyl)-1-[4-(isopentyloxy)benzyl]-3-(4-chloro-2,6-dimethyl-                                            82-85         phenyl)urea    457  1-(n-Heptyl)-1-[4-(isopentyloxy)benzyl]-3-(2,4-difluorophenyl)urea                                            oil    458  1-(n-Heptyl)-1-[4-(2-methylbutyl)benzyl]-3-(2,4-difluorophenyl)urea                                            oil    459  1-(n-Heptyl)-1-[4-(2-methylbutyl)benzyl]-3-(2,4,6-trifluorophenyl)-                                            solid         urea    460  1-(n-Heptyl)-1-[4-(2-isopropylthioethyl)benzyl]-3-(4-chloro-2,6-                                            112-113         dimethylphenyl)urea    461  1-(n-Heptyl)-1-[4-(2-isopropylsulfonylethyl)benzyl]-3-(2,4-difluoro-                                            oil         phenyl)urea    462  1-(n-Heptyl)-1-[4-(2-isopropylsulfonylethyl)benzyl]-3-(4-chloro-2,6-                                            130-131         dimethylphenyl)urea    463  1-(n-Heptyl)-1-[4-(2,3-dimethylpentyl)benzyl]-3-(2,4-difluorophenyl)-                                            oil         urea    464  1-(n-Heptyl)-1-[4-(2-isopropylthioethyl)benzyl]-3-(2,4-difluoro-                                            oil         phenyl)urea    465  1-(n-Heptyl)-1-[4-(2-isopropylsulfinylethyl)benzyl]-3-(4-chloro-2,6-                                            oil         dimethylphenyl)urea    466  1-(n-Heptyl)-1-[4-(2,3-dimethylpentyl)benzyl]-3-(2,4,6-trifluoro-                                            oil         phenyl)urea    467  1-(n-Heptyl)-1-[4-(1,2-dimethylpropyl)benzyl]-3-(2,4-difluorophenyl)-                                            32-34         urea    468  1-(n-Heptyl)-1-[4-(1,2-dimethylpropyl)benzyl]-3-(2,4,6-trifluoro-                                            69-70         phenyl)urea    469  1-(n-Heptyl)-1-[4-(1,2-dimethylpropyl)benzyl]-3-(4-chloro-2,6-                                            108-  110         dimethylphenyl)urea    470  1-(n-Heptyl)-1-[4-(2,3-dimethylpentyl)benzyl]-3-(4-chloro-2,6-                                            oil         dimethylphenyl)urea    471  1-(n-Heptyl)-1-[4-(2-isopropylsulfinylethyl)benzyl]-3-(2,4-difluoro-                                            oil         phenyl)urea    472  1-(n-Heptyl)-1-[4-(isopentyloxymethyl)benzyl]-3-(2,4-difluorophenyl)-                                            oil         urea    473  1-(n-Heptyl)-1-[4-(isopentyloxymethyl)benzyl]-3-(2,4,6-trifluoro-                                            oil         phenyl)urea    474  1-(n-Heptyl)-1-[4-(isopentyloxymethyl)benzyl]-3-(4-chloro-2,6-                                            oil         dimethylphenyl)urea    __________________________________________________________________________

EXAMPLE 475 1-Benzyl-1-(n-butyl)-3-(3-chlorophenyl)urea

A solution of 1.56 g of phenyl chloroformate in 50 ml of ether was addeddropwise to a stirred solution of 2.55 g of 3-chloroaniline in 35 ml ofether. The mixture was stirred for one hour at room temperature and thenfiltered. The filtrate was evaporated and the residue crystallized fromhexane to yield phenyl N-(3-chlorophenyl)-carbamate.

A solution of 1.46 g of phenyl N-(3-chlorophenyl)carbamate in 15 ml oftetrahydrofuran was added to a solution of 1.92 g ofN-benzyl-n-butylamine in 20 ml of tetrahydrofuran and the mixturestirred under reflux for 24 hours. The mixture was diluted with hexaneand the precipitate collected by filtration. Recrystallization frompentane afforded 1-benzyl-1-(n-butyl)-3-(3-chlorophenyl)urea, m.p.69°-70° C.

EXAMPLE 476 1-Benzyl-1-(n-butyl)-3-(4-carboxyphenyl)urea

A solution of 5.30 g of 1-benzyl-1-(n-butyl)-3-(4-carboethoxyphenyl)ureain 100 ml of ethanol is treated with 25 ml of 1N aqueous sodiumhydroxide, stirred under reflux for 16 hours, allowed to cool, acidifiedwith 1N hydrochloric acid, and filtered. The solid is recrystallizedfrom ethanol to yield 1-benzyl-1-(n-butyl)-3-(4-carboxyphenyl)urea as awhite solid.

EXAMPLE 477 1-Benzyl-1-(n-butyl)-3-(2-hydroxy-3-chlorophenyl)urea

A solution of 1.73 g of1-benzyl-1-(n-butyl)-3-(2-methoxy-3-chlorophenyl)urea and 1.0 ml ofboron tribromide in 40 ml of methylene chloride was stirred at ambienttemperature for 3 days and diluted with water. The organic layer wasseparated, dried, and evaporated. The residue was crystallized fromhexane to yield 1-benzyl-1-(n-butyl)-3-(2-hydroxy-3-chlorophenyl)urea,m.p. 59°-62° C.

EXAMPLE 478 N-(2-Chlorobenzyl)-3-methoxyphenylacetamide

A mixture of 12.5 g of 3-methoxyphenylacetic acid, 21.2 g of2-chlorobenzylamine, 15.1 g of triethylamine, 19.3 ml ofborontrifluoride etherate, and 500 ml of toluene was stirred underreflux for 18 hours using a Dean-Stark moisture trap and allowed tocool. The mixture was extracted with aqueous sodium hydroxide, dilutehydrochloric acid, and water. The remaining organic solution was thenevaporated and the residue crystallized from hexane to yieldN-(2-chlorobenzyl)-3-methoxyphenylacetamide as a yellow solid, m.p.89°-91° C.

EXAMPLE 479 N-(n-Butyl)-2-chlorobenzylamine

A solution of 21.2 g of N-(n-butyl)-2-chlorobenzamide in 100 ml oftetrahydrofuran was added with cooling to 200 ml of 1M borane intetrahydrofuran and the mixture was stirred under reflux for 18 hours,allowed to cool, and treated with 6N hydrochloric acid. The organicsolvent was evaporated, and the residue was partitioned between etherand aqueous sodium hydroxide solution. The ether layer was separated,dried, and evaporated. The residue was distilled to yieldN-(n-butyl)-2-chlorobenzylamine as a colorless liquid, b.p. 65°-75° C.at 60μ.

EXAMPLE 480 4-Butyl-N-(6-hydroxyphexyl)benzamide

To a stirred solution of 23.5 g of 6-amino-1-hexanol and 30 g oftriethylamine in 200 ml of dichloromethane, cooled in an ice bath, wasadded dropwise a solution of 43.3 g of p-butylbenzoyl chloride in 100 mlof dichloromethane. The mixture was allowed to stir at room temperaturefor 16 hours. Then the mixture was washed in succession with water,saturated sodium carbonate, water, and finally brine. The organic layerwas dried over anhydrous sodium sulfate and evaporated in vacuo. Theresidue was triturated, filtered, and rinsed with cold hexane and gave47.5 g of the desired product in 61% yield as a beige solid, m.p.80°-81° C.

Additional amides (Examples 481-486), which are listed in Table VI, wereprepared according to the procedure of Example 480.

                                      TABLE VI    __________________________________________________________________________    Example         Amide                Description                                       MP or BP                                               % Yield    __________________________________________________________________________    481  4-Butyl- .sub.--N--[2-(2-hydroxyethoxy)ethyl]-                              Yellow Oil       93         benzamide    482   .sub.--N--Heptyl-2-furancarboxamide                              Colorless Liquid                                       121° C./0.1 mm                                               99    483  4-Butoxy- .sub.--N--(2-thienylmethyl)benzamide                              White Crystals                                       128-130° C.                                               72    484   .sub.--N--(2-Thienylmethyl)heptanamide                              Colorless Solid                                       62-63° C.                                               82    485   .sub.--N--[(4-Butylphenyl)methyl]-5-(trimethyl-                              White Solid                                       72-74° C.                                               55         silyl)pentanamide    486  3,3-Dimethylbutyl-2-thiophenecarboxamide                              White Solid                                       145-146° C.                                               91    __________________________________________________________________________

EXAMPLE 487 6-[[(4-Butylphenyl)methyl]amino]-1-hexanol

To a solution of 45.0 g of the product of Example 1 in 200 ml oftetrahydrofuran, cooled in an ice bath was added dropwise, 325 ml ofborane (1M boranetetrahydrofuran complex). The resulting mixture washeated at reflux for 16 hours. The mixture was cooled to roomtemperature and 57 ml of 6N hydrochloric acid was added dropwise overargon gas. The solvent was evaporated in vacuo. The residue was slurriedin water while adding sodium hydroxide pellets until the pH was basic.The aqueous solution was extracted with diethyl ether. The etheralextract was dried over anhydrous sodium sulfate, then evaporated invacuo, and gave 33.7 g of the desired product in 79% yield, as a yellowoil.

EXAMPLE 488 4-Butyl-N-[5-(trimethylsilyl)pentyl]benzenemethanamine

To a suspension of 2.5 g of lithium aluminum hydride in 100 ml ofanhydrous tetrahydrofuran was added dropwise a solution of 5.0 g ofN-[(4-butylphenyl)methyl]-5-(trimethylsilyl)pentanamide intetrahydrofuran. The resulting mixture was heated at reflux for 16hours. The mixture was cooled, and the complex was decomposed by thecautious portionwise addition of sodium sulfate decahydrate. The mixturewas stirred for 1/2 hour and then filtered. The solid was washed withtetrahydrofuran, and the filtrate was dried with anhydrous magnesiumsulfate and filtered. The filtrate was evaporated to dryness and gave4.53 g of the desired product as a colorless liquid, in 95% yield.

EXAMPLE 489 3,3-Dimethylbutyl-2-thiophenemethanamine

To a solution of 17.0 ml of Vitride® T [sodiumdihydrobis(2-methoxyethoxy)aluminate (70% solution in toluene)] in 50 mlof toluene, was added dropwise a solution of 5.0 g of3,3-dimethylbutyl-2-thiophene carboxamide in 50 ml of driedtetrahydrofuran. The resulting mixture was heated at reflux for 2 hours,then cooled. The complex was decomposed by adding dropwise 30 ml of 2.5Nsodium hydroxide. The mixture was stirred for one hour. The layers wereseparated and the organic layer was washed with brine, dried overanhydrous magnesium sulfate and filtered. The filtrate was evaporated invacuo and gave a light brown liquid. Kugelrohr distillation (75° C./0.15mm of mercury) gave 4.0 g (82% yield) of the desired product.

Additional secondary amines are listed in Table VII and were prepared bythe procedures described in Examples 487-489.

                                      TABLE VII    __________________________________________________________________________         Example               Amide    Example         Procedure               Precursor                     Amine         Description                                         MP or BP   % Yield    __________________________________________________________________________    490  487   Ex. 482                      .sub.--N--Heptyl-2-furanmethan-                                   Colorless                                         70-75° C./0.08                                                    67                     amine         Liquid    491  488   Ex. 485                     4-Butyl- .sub.--N--[5-(trimethyl-                                   Colorless        95                     silyl)pentyl]benzenemeth-                                   Liquid                     anamine    492  487   Ex. 481                     2-[2-[[(4-Butylphenyl)-                                   Colorless        83                     methyl]amino]ethoxy]-                                   Liquid                     ethanol    493  488   Ex. 484                      .sub.--N--Heptyl-2-thiophenemeth-                                   Colorless                                         90-100° C./0.20                                                    96                     anamine       Liquid    494  488   Ex. 483                      .sub.--N--[(4-Butoxyphenyl)meth-                                   Colorless        92                     yl]-2-thiophenemethanamine                                   Liquid    __________________________________________________________________________

EXAMPLE 495[1-[(4-Butylphenyl)methyl]-3-(2,4-dimethylphenyl)-1-(6-hydroxyhexyl)urea

To a stirred solution of 1.46 g of 2,4-dimethylphenyl isocyanate in 100ml of hexane was added a solution of 2.63 of6-[[(4-butylphenyl)methyl]amino]-1-hexanol (prepared as described inExample 489) in 500 ml of hexane. The mixture was stirred at roomtemperature for 2 hours. Evaporation gave a gum. The gum was purified bychromatography to yield 2.81 g of the desired product as a colorles gum.

Additional ureas and thioureas of the present invention were prepared bythe reaction of an appropriate arylisocyanate or arylisothiocyanate witha hereinbefore prepared secondary amine by the method of Example 495.The compounds appear in Table VIII.

                                      TABLE VIII    __________________________________________________________________________         Amine                         MP or BP    Example         Precursor               Product           Description                                       °C.                                                % Yield    __________________________________________________________________________    496  Ex. 490               1-(2-Furanylmethyl)-1-heptyl-3-                                 White Solid                                       65-67    86               (2,4,6-trimethylphenyl)urea    497  Ex. 490               1-(2-Furanylmethyl)-1-heptyl-3-                                 Yellow Oil                                       135-140/0.175 mm                                                87               (2,4,6-trichlorophenyl)urea    498  Ex. 487               1-[(4-Butylphenyl)methyl]-3-(4-                                 Colorless      58               chloro-2-methylphenyl)-1-(6-hydroxy-                                 Oil               hexyl)urea    499  Ex. 487               1-[(4-Butylphenyl)methyl]-1-(6-                                 Colorless      63               hydroxyhexyl)-3-(2,4,5-trimethyl-                                 Gum               phenyl)urea    500  Ex. 492               1-[(4-Butylphenyl)methyl]-3-(2,4-                                 Colorless      46               dimethylphenyl)-1-[2-(2-hydroxy-                                 Gum               ethoxy)ethyl]urea    501  Ex. 492               1-[(4-Butylphenyl)methyl]-1-[2-(2-                                 White Solid                                       84-86    89               hydroxyethoxy)ethyl]-3-(2,4,5-tri-               methylphenyl)urea    502  Ex. 493               1-Heptyl-1-(2-thienylmethyl)-3-                                 White Solid                                       84-85    94               (2,4,5-trimethylphenyl)urea    503  Ex. 493               1-Heptyl-1-(2-thienylmethyl)-3-                                 White Solid                                       72-73    72               (2,4,6-trichlorophenyl)urea    504  Ex. 494               1-[(4-Butoxyphenyl)methyl]-1-(2-                                 White Solid                                       114-115  99               thienylmethyl)-3-(2,4,5-trimethyl-               phenyl)urea    505  Ex. 487               1-[(4-Butylphenyl)methyl]-1-(6-                                 Light          65               hydroxyhexyl)-3-(2,4,6-trichloro-                                 Brown               phenyl)urea       Oil    506  Ex. 491               1-[(4-Butylphenyl)methyl]-3-(4-                                 Colorless                                       165-170/0.080 mm                                                77               chloro-2-methylphenyl)-1-[5-(tri-                                 Oil               methylsilyl)pentyl]urea    507  Ex. 491               1-[(4-Butylphenyl)methyl]-3-(2,4-                                 Colorless                                         165/0.080 mm                                                82               difluorophenyl)-1-[5-(trimethyl-                                 Oil               silyl)pentyl)urea    508  Ex. 489               3-(2,4-Difluorophenyl)-1-(3,3-di-                                 Colorless                                         75/0.150 mm                                                73               methylbutyl)-1-(2-thienylmethyl)urea                                 Liquid    509  Ex. 489               3-(4-Chloro-2-methylphenyl)-1-(3,3-                                 White Solid                                       111-113  64               dimethylbutyl)-1-(2-thienylmethyl)-               urea    510  Ex. 489               1-(3,3-Dimethylbutyl)-1-(2-thienyl-                                 White Solid                                       118-120  91               methyl)-3-(2,4,6-trichlorophenyl)-               urea    __________________________________________________________________________

Other ureas and thioureas which may be prepared by the method describedin Example 495 include:

1-[(4-Butylphenyl)methyl]-3-[(2-methoxy-5-methyl)phenyl]-1-[5-(trimethylsilyl)pentyl]urea

1-[(4-Butylphenyl)methyl]-3-[(4-carboethoxy-2-methyl)phenyl]-1-[5-(trimethylsilyl)pentyl]urea

1-[(4-n-Butylphenyl)methyl]-3-[(4-carboxy-2-methyl)phenyl]-1-[5-(trimethylsilyl)pentyl]urea

EXAMPLE 511 Phenyl-N-(2,4-difluorophenyl)carbamate

To a solution of 1.94 g of 2,4-difluoroaniline in 20 ml of toluene wasadded dropwise 1.29 g of phenyl chloroformate. The mixture was stirredfor 15 minutes, washed with three 10 ml portions of water, dried overanhydrous sodium sulfate, and filtered through a pad of diatomaceousearth. The filtrate was evaporated in vacuo to give an oil whichsolidified on cooling. The solid was crystallized from hexane to give1.73 g of the desired product as pale tan crystals in 93% yield, mp82°-84° C.

EXAMPLE 5121-[(4-Butylphenyl)methyl]-3-(2,4-difluorophenyl)-1-(6-hydroxyhexyl)urea

A mixture of 1.58 g of 6-[[(4-butylphenyl)-methyl]amino]-1-hexanol and1.5 g of phenyl-N-(2,4-difluorophenyl)carbamate in 40 ml of toluene washeated at reflux for 5 hours. The reaction mixture was cooled andallowed to stand at room temperature for 16 hours. The solution waswashed with 3N aqueous hydrochloric acid, brine, 1N aqueous sodiumhydroxide and brine again, then was dried over anhydrous magnesiumsulfate and filtered. The filtrate was evaporated in vacuo and gave ayellow oil. The oil was treated by preparative high pressure liquidchromatography and gave 0.93 g (37%) of the desired product as acolorless oil.

EXAMPLE 513 Phenyl[(4-butylphenyl)methyl][6-hydroxyhexyl]carbamate

To a stirred solution of 7.26 g of6-[[(4-butylphenyl)methyl]amino]-1-hexanol in 50 ml of toluene was addeda solution of 2.16 g of phenyl chloroformate in 20 ml of toluene, withthe immediate precipitation of a white solid. The resulting mixture wasstirred at room temperature for 24 hours. The mixture was filtered, andthe filter was washed with toluene. The combined filtrate and wash wasevaporated in vacuo and gave a colorless oil. The oil was Kugelrohrdistilled and gave 3.5 g of the desired product in 66% yield as acolorless oil, bp 180°-195° C./0.06 mm of mercury.

EXAMPLE 514 5-(Trimethylsilyl)pentanoic acid

Preparation of Grignard reagent:

To a suspension of 1.58 g of magnesium turnings in 7.0 ml of freshlydistilled tetrahydrofuran (distilled over benzophenone and sodium metal)was added about 2.0 ml of bromomethyltrimethylsilane under argon. A fewcrystlas of iodine were added and the mixture was heated with a hot airgun. The reaction began immediately and an additional amount ofbromomethyltrimethylsilane (for a total of 10.03 g) was added dropwiseover a 20 minute period. The mixture was stirred and heated at an oilbath temperature of 70°-80° C. for an additional 3 hours, then cooled atroom temperature and allowed to stand.

In another flask a solution of 9.02 g of 4-bromobutyric acid in 30 ml ofdry, freshly distilled, tetrahydrofuran was stirred and cooled at -30°C. under argon, the 19.0 ml of methyl magnesium chloride was added tothe solution while maintaining the temperature at -20° C. The mixturewas stirred at -20° C. for 10 minutes, then a solution of dilithiumtetrachlorocuprate (prepared by dissolving 85.4 mg of lithium chlorideand 173 mg of cupric chloride in 8.0 ml of tetrahydrofuran) was added tothe reaction mixture, and stirring was continued for 5 minutes longer at-20° C. Then the hereinabove prepared Grignard reagent in 7.0 ml oftetrahydrofuran (kept in solution by warming) was added dropwise at -20°C. The resulting mixture was stirred at -20° C. for one hour more, thenat ambient temperature for 16 hours.

The reaction mixture was then poured into a mixture of ethyl acetate:10%sulfuric acid (200 ml:200 ml) and stirred for 5 minutes. The two layerswere separated and the organic layer was washed three times with brine,dried over anhydrous magnesium sulfate and filtered. The volatiles wereevaporated in vacuo to leave a brown liquid. The liquid was distilledusing a Vigreux column and an oil bath temperature of 150°-160° C. forthe third fraction which gave 7.5 g of the desired product (bp139°-139.5° C./10 mm) as a pinkish liquid (80% yield).

EXAMPLE 5151-[(4-Butylphenyl)methyl]-1-[6-[(methylsulfonyl)oxy]-hexyl]-3-[(2,4,5-trimethylphenyl)methyl]urea

To a cooled solution (0°-5° C.) of 10.0 g of1-[(4-butylphenyl)methyl]-1-6-(hydroxyhexyl)-3-(2,4,5-trimethylphenyl)ureaand 7.3 ml (5.3 g) of triethylamine in 125 ml of dichloromethane wasadded dropwise a solution of 2.4 ml of methanesulfonyl chloride in 25 mlof dichloromethane. The resulting solution was gradually warmed to roomtemperature and stirred for 3 hours. The mixture was poured intoice-water. The organic layer was separated and washed in succession with10% aqueous hydrochloric acid, water, a saturated aqueous solution ofsodium bicarbonate, and brine. The organic solution was then dried overanhydrous magnesium sulfate and filtered. The filtrate was evaporated todryness to yield 10.4 g (88%) of the desired product as a light brownoil.

EXAMPLE 5161-[(4-Butylphenyl)methyl]-1-[6-(methylsulfonyloxy)-hexyl]-3-(2,4,6-trichlorophenyl)urea

To a cooled solution (0°-5° C.) of 4.0 g of1-[(4-butylphenyl)methyl]-1-(6-hydroxyhexyl)-3-(2,4,6-trichlorophenyl)ureaand 2.6 ml of triethylamine in 90 ml of dichloromethane was addeddropwise a solution of 0.8 ml of methanesulfonyl chloride in 10 ml ofdichloromethane. The resulting solution was allowed to come to roomtemperature and was stirred for 16 hours. The procedure of Example 515was continued and gave 4.5 g of the desired product as a light yellowoil in 97% yield.

EXAMPLE 5171-[(4-Butylphenyl)methyl]-3-(4-chloro-2-methylphenyl)-1-[6-[(methylsulfonyl)oxy]hexyl]urea

To a cooled solution (0°-5° C.) of 5.24 g of1-[(4-butylphenyl)methyl]-3-(4-chloro-2-methylphenyl)-1-(6-hydroxyhexyl)ureaand 4.0 ml of triethylamine in 65 ml of dichloromethane was addeddropwise a solution of 1.2 ml of methanesulfonyl chloride in 10 ml ofdichloromethane. The resulting solution was gradually warmed to roomtemperature, then was stirred for 16 hours. The procedure of Example 515was continued and gave 6.0 g of the desired product as a light brown oilin 97% yield.

EXAMPLE 5181-[(4-Butylphenyl)methyl]-1-(6-cyanohexyl)-3-(2,4,5-trimethylphenyl)urea

A mixture of 2.0 g of1-[(4-butylphenyl)methyl]-1-[6-[(methylsulfonyl)oxy]hexyl]-3-[(2,4,5-trimethylphenyl)methyl]urea,0.5 g of sodium cyanide and 5.0 ml of dimethyl sulfoxide was heated atan oil bath temperature of 60°-70° C. for 11/2 hours. The mixture wascooled and poured into ice-water. The mixture was extracted with ether.The etheral layer was separated, washed with brine, dried over magnesiumsulfate, and filtered. The filtrate was evaporated to dryness to yield1.45 g (84% ) of the desired product as a light brown oil.

EXAMPLE 5191-[(4-Butylphenyl)methyl]-1-(6-cyanohexyl)-3-(2,4,6-trichlorophenyl)urea

A mixture of 2.2 g ofN-[(4-butylphenyl)methyl]-N-[6-(methylsulfonyloxy)hexyl]-N-(2,4,6-trichlorophenyl)-urea,0.5 g of sodium cyanide, and 3.0 ml of dried dimethyl sulfoxide washeated at an oil bath temperature of 60°-70° C. for 20 hours. Themixture was poured into water and extracted with dichloromethane. Theprocedure of Example 518 was continued and gave 1.65 g (85% yield) ofthe desired product as a light brown oil.

EXAMPLE 5201-[(4-Butylphenyl)methyl]-3-(4-chloro-2-methylphenyl)-1-(6-cyanohexyl)urea

A mixture of 2.0 g of1-[(4-butylphenyl)methyl]-3-(4-chloro-2-methylphenyl)-1-[6-[(methylsulfonyl)oxy]-hexyl]urea,0.5 g of sodium cyanide, and 3.0 ml of dimethyl sulfoxide was heated atan oil bath temperature of 60°-70° C. for 16 hours. The mixture waspoured into water and extracted with dicholormethane. The procedure ofExample 518 was continued and gave 1.5 g (88% yield) of the desiredproduct as a brown oil.

EXAMPLE 5211-[(4-Butylphenyl)methyl]-1-(6-chlorohexyl)-3-(2,4,5-trimethylphenyl)urea

A mixture of 2.0 g of1-[(4-butylphenyl)methyl]-1-[6-[(methylsulfonyl)oxy]hexyl]-3-[(2,4,5-trimethylphenyl)methyl]urea,0.74 g of potassium chloride, and 4.0 ml of dimethyl sulfoxide washeated at an oil bath temperature of 60° C. for 12 hours. The mixturewas cooled and poured into ice-water. The mixture was extracted withether. The ether layer was washed with brine, dried over anhydrousmagnesium sulfate, and filtered. The filtrate was evaporated in vacuo toyield 1.5 g of a light brown oil. The oil was purified by chromatographyto yield 1.2 g of the desired product (68% yield) as a colorless oil.

EXAMPLE 5221-[(4-Butylphenyl)methyl]-1-(6-chlorohexyl)-3-(2,4,6-trichlorophenyl)urea

A mixture of 1.9 g of1-[(4-butylphenyl)methyl]-1-[6-[(methylsulfonyl)oxy]hexyl]-3-(2,4,6-trichlorophenyl)]-urea,0.6 g of potassium chloride, and 3.0 ml of dried dimethyl sulfoxide washeated at an oil bath temperature of 60°-70° C. for 20 hours. Theextraction and chromatography procedures of Example 521 were followed togive 1.1 g of the desired product as a colorless oil.

EXAMPLE 5231-[(4-Butylphenyl)methyl]-1-(6-chlorohexyl)-3-(4-chloro-2-methylphenyl)urea

A mixture of 2.0 g of1-[(4-butylphenyl)methyl]-3-(4-chloro-2-methylphenyl)-1-[6-[(methylsulfonyl)oxy]-hexyl]urea,0.74 g of potassium chloride, and 3.0 ml of dimethyl sulfoxide washeated at an oil bath temperature of 60°-80° C. for 16 hours. Themixture was diluted with water and extracted with dichloromethane. Theorganic layer was washed with three 40 ml portions of brine, dried overanhydrous magnesium sulfate and filtered. The filtrate was evaporated invacuo to yield 1.5 g of a brown oil. The oil was purified bychromatography to yield 1.5 g of the desired product as a light yellowoil in 86% yield.

EXAMPLE 524 1-[(4-Butylphenyl)methyl]-3-(2-hydroxy-5-methylphenyl)-1-85-(trimethylsilyl)pentyl]urea

To an ice cold solution of 10 ml of borontribromide in dichloromethaneis added dropwise a solution of 2.34 g of1-[(4-butylphenyl)methyl]-3-[(2-methoxy-5-methyl)-phenyl]-1-[5-(trimethylsilyl)pentyl]ureain 20 ml of dichloromethane. The mixture is allowed to stir at roomtemperature for 24 hours, then is diluted with 50 ml of water andstirred for 3 hours. Two layers are separated. The organic layer iswashed with brine, dried over anhydrous magnesium sulfate and filtered.The filtrate is evaporated to dryness to yield an oil. The oil ispurified by Kugelrohr distillation to give the desired product.

EXAMPLE 5251-[(4-Butylphenyl)methyl]-3-[(4-carboxy-2-methyl)-phenyl]-1-[5-(trimethylsilyl)pentyl]urea

A solution of 1.28 g of1-[(4-butylphenyl)methyl]-3-](4-carboethoxy-2-methyl)phenyl]-1-[5-(trimethylsilyl)pentyl]ureain 30 ml of ethanol is treated with 5.0 ml of 1N sodium hydroxide. Theresulting solution is stirred under reflux for 16 hours. The mixture iscooled and acidified with 1N hydrochloric acid. The precipitated solidis collected by filtration, washed with water, and dried. The desiredproduct is crystallized from ethanol.

EXAMPLE 526 4-Butylbenzamide

To a stirred solution of 200 ml of aqueous ammonium hydroxide was addeddropwise 35 ml of 4-butylbenzoyl chloride. The resulting mixture wasstirred at room temperature for several hours. The white solid wascollected by filtration, washed with water, then hexane, and dried invacuo at 60° C. to give 33.4 g (99% yield) of the desired product, mp135°-136° C.

EXAMPLE 527 4-Butylbenzenemethanamine

To a suspension of 15 g of lithium aluminum hydride in 200 ml ofanhydrous ethyl ether under argon was added, at room temperature, asolution of 32. 0 g of 4-butylbenzamide in 200 ml of freshly distilledtetrahydrofuran. The resulting mixture was stirred at room temperaturefor one hour and then heated at reflux for 20 hours. The mixture wascooled and sodium sulfate decahydrate was cautiously added portionwiseto the mixture until it was colorless. The mixture was stirred for 30minutes. The mixture was filtered and the filter was washed with ether.The filtrate was evaporated in vacuo to yield 29 g (99% yield) of aliquid. The liquid was distilled by Kugelrohr distillation, bp 85°C./0.070 mm of mercury, to give the desired product as a colorlessliquid.

EXAMPLE 528 N-Heptyl-4-n-butylbenzamide

To a cold solution of 16 g of n-heptylamine and 29.0 ml of triethylaminein 300 ml of methylene chloride was added dropwise a solution of 27.4 gof 4-butylbenzoylchloride in 100 ml of methylene chloride. The resultingmixture was stirred at room temperature for 41/2 hours and diluted withwater. The organic layer was washed with 1N sodium hydroxide, brine,dried, and evaporated. The residual solid was recrystallized from hexaneto yield N-heptyl-4-n-butylbenzamide, mp 37°-38° C.

EXAMPLE 529 N-Heptyl-4-n-butylbenzenemethanamine

A solution of 38.0 g of N-heptyl-4-n-butylbenzamide and 280 ml ofborane-tetrahydrofuran complex in 120 ml of anhydrous tetrahydrofuranwas refluxed for 18 hours, allowed to cool, and treated with 6Nhydrochloric acid. The organic solvent was evaporated and the residuewas partitioned between ether and aqueous sodium hydroxide solution. Theether layer was separated, dried, and evaporated. The residue wasdistilled to yield N-heptyl-4-n-butylbenzenemethanamine as a colorlessliquid, bp 115° C. at 80μ.

EXAMPLE 5301-[(4-Butylphenyl)methyl]-1-(n-heptyl)-3-[2,4-difluorophenyl]urea

A solution of 1.55 g of 2,4-diflurophenylisocyanate in hexane was addedto a solution of 2.61 g of N-heptyl-4-butylbenzenemethanamine in 15 mlof hexane and the solution was stirred at room temperature for 4 hours,then evaporated. The residual oil was distilled to yield1-[(4-butylphenyl)methyl]-1-(n-heptyl)-3-[2,4-difluorophenyl]urea as acolorless oil, bp 160°-165° C./120μ.

EXAMPLE 531 N-[3,3-Dimethylbutyl]-4-n-butylbenzamide

To a solution of 4.94 g of 4-butylbenzoylchloride in 20 ml of methylenechloride was added dropwise a solution of 2.53 g of3,3-dimethylbutylamine and 5.1 g of triethylamine in 80.0 ml ofmethylene chloride. The resulting mixture was stirred at roomtemperature for 18 hours. The mixture was diluted with water, and theorganic layer was washed with 6N hydrochloric acid, water, 2N sodiumhydroxide, brine, dried, and evaporated to dryness to yield an oil whichsolidified on standing. The solid was triturated with hexane, collectedby filtration, and dried to yieldN-[3,3-dimethylbutyl]-4-n-butylbenzamide as a white solid, mp 70°-71° C.

EXAMPLE 532 N-[3,3-Dimethylbutyl]-4-n-butylbenzenemethanamine

A solution of 7.5 g of N-[3,3-dimethylbutyl]-4-n-butylbenzenemethanaminein 40 ml of tetrahydrofuran was added dropwise to a suspension of 3.3 gof lithium aluminium hydride in 80 ml of tetrahydrofuran. The resultingmixture was refluxed for 18 hours, cooled, and the complex wasdecomposed by adding sodium sulfate decahydrate portionwise until acolorless mixture was obtained. The mixture was stirred for anadditional half hour, filtered, and the filtrate was evaporated todryness to yield a liquid. The liquid was distilled to yieldN-[3,3-dimethylbutyl]-4-n-butylbenzenemethanamine as a colorless liquid,bp 80°-90° C. at 80μ.

EXAMPLE 533 Phenyl-N-(4-chloro-2,6-dimethylphenyl)carbamate

A solution of 2.56 g of phenyl chloroformate in 20 ml of toluene wasadded to a cold solution of 2.47 g of 4-chloro-2,6-dimethylaniline and2.4 ml of N,N-dimethylaniline in 80 ml of toluene. The resulting mixturewas stirred at room temperature for 11/2 hours and then diluted withwater. The organic layer was washed with 3N hydrochloric acid, brine,dried, and evaporated. The residual solid was crystallized fromethylacetate:hexane to yieldphenyl-N-(4-chloro-2,6-dimethylphenyl)carbamate, mp 158°-160° C.

EXAMPLE 5341-[(4-Butylphenyl)methyl]-1-[3,3-dimethylbutyl]-3-[4-chloro-2,6-dimethylphenyl]urea

A solution of 825 mg of phenyl-N-(4-chloro-2,6-dimethylphenyl]carbamateand 740 mg of N-[3,3-dimethylbutyl]-4-n-butylbenzenemethanamine in 40 mlof toluene was refluxed for 1 hour, cooled, and the solution was washedwith 1N sodium hydroxide, brine, dried, and evaporated to dryness toyield a solid. The solid was recrystallized from hexane to yield1-[(4-butylphenyl)methyl]-1-[3,3-dimethylbutyl]-3-[4-chloro-2,6-dimethylphenyl]ureaas a white solid, mp 138°-139° C.

EXAMPLE 535 p-Neopentylbenzoic acid

To a cooled suspension of 43.0 g of anhydrous aluminum chloride in 250ml of methylene chloride was added 40.0 g of oxalyl chloride over aperiod of 25 minutes. The resulting mixture was stirred for 5 minutesand then 43.2 g of neopentylbenzene was added dropwise maintaining atemperature of 0°-50° C. over a period of 35 minutes. The dark redmixture was stirred at an ambient temperature and then heated slowly toreflux for 3 hours, cooled, and poured into a mixture of 250 g of iceand 188 ml of concentrated hydrochloric acid. The mixture was stirredfor 1/2 hours, and two layers were separated. The aqueous layer wasextracted with methylene chloride and the combined organic layers wereevaporated to yield a brown oily residue. The residue was heated andstirred under reflux with 200 ml of 10N sodium hydroxide, 150 ml ofwater, and 250 ml of ethyl alcohol for 20 minutes, cooled, and themixture was extracted with ether. The aqueous layer was acidified withconcentrated hydrochloric acid and stirred for 1 hour. The solid wascollected by filtration, washed with water, dissolved in ethyl acetate,the aqueous layer was discarded, dried and evaporated to yield a solid.The solid was crystallized from acetone to yield p-neopentylbenzoic acidas a beige solid, mp 191°-193° C.

EXAMPLE 536 N-(3,3-Dimethylbutyl)-4-(2,2-dimethylpropyl)benzamide

To a cold solution of 5.26 g of 3,3-dimethylbutylamine and 21.0 ml oftriethylamine in 180 ml of methylene chloride was added dropwise asolution of p-neopentylbenzoylchloride in 20 ml of methylene chloride.The resulting mixture was stirred at room temperature for 5 hours anddiluted with water. The organic layer was washed with 3N hydrochloricacid, water, 1N sodium hydroxide, brine, dried, and evaporated to yielda solid. The solid was recrystallized from ethylacetate:hexane to yieldN-(3,3-dimethylbutyl)-4-(2,2-dimethylpropyl)benzamide as a beige solid,mp 124°-126° C.

EXAMPLE 537N-(3,3-Dimethylbutyl)-4-(2,2-dimethylpropyl)benzenemethanamine

A solution of 13.0 g ofN-(3,3-dimethylbutyl)-4-(2,2-dimethylpropyl)benzenemethanamine in 50 mlof tetrahydrofuran was added dropwise to a suspension of 6.0 g oflithium aluminum hydride in 200 ml of tetrahydrofuran and the resultingmixture was heated to reflux for 18 hours, then cooled. The mixture wasdecomposed by adding sodium sulfate decahydrate portionwise until acolorless mixture was obtained. The mixture was stirred for anadditional half hour, filtered, and the filtrate was evaporated to yieldan oil. The oil was distilled to yieldN-(3,3-dimethylbutyl)-4-(2,2-dimethylpropyl)benzenemethanamine as acolorless oil, bp 100°-110° C. at 100μ.

EXAMPLE 5381-[3,3-Dimethylbutyl]-1-[[4-(2,2-dimethylpropyl)phenyl]methyl]-3-[4-chloro-2,6-dimethylphenyl]urea

A solution of 825 mg of phenyl-N-(4-chloro-2,6-dimethylphenyl)carbamateand 782 mg ofN-(3,3-dimethylbutyl)-4-(2,2-dimethylpropyl)benzenemethanamine in 40 mlof toluene was heated to reflux for 1 hour, cooled, and the solution waswashed with 1N sodium hydroxide, brine, dried, and evaporated to drynessto yield a solid. The solid was recrystallized from hexane to yield1-[3,3-dimethylbutyl[-1-[[4-(2,2-dimethylpropyl)phenyl]methyl]-3-]4-chloro-2,6-dimethylphenyl]ureaas a white solid, mp 148°-150° C.

I claim:
 1. A method of reducing the cholesterol ester content of anarterial wall, inhibiting atherosclerotic lesion development, and/ortreating hyperlipidemia in a mammal in need of such treatment whichcomprises administering to said mammal an effective amount of a compoundof the formula: ##STR8## wherein X represents at least one substituentselected from the group consisting of (C₁ -C₄)alkyl, (C₁ -C₄)alkenyl,(C₁ -C₄)alkynyl, phenoxy, mercapto, amino, (C₁ -C₄)alkylamino, di(C₁-C₄)alkylamino, halo, trihalomethyl, (C₁ -C₄)alkanoyl, benzoyl, (C₁-C₄)alkanamido, haloacetamido, nitro, cyano, carboxy, (C₁-C₄)carboalkoxy, carbamoyl, sulfamyl, methylenedioxy, phenyl,ortho-phenylene, tolyl, benzyl, halobenzyl, methylbenzyl; Y is selectedfrom the group consisting of oxygen and sulfur; R₁ and R₂ are differentand are independently selected from the group consisting of (C₄-C₁₂)alkyl, (C₄ -C₁₂)alkenyl, (C₄ -C₁₂)alkynyl, C₄ -C₁₂)cycloalkylalkyl, (C₇ -C₁₄)aralkyl, and (C₇ -C₁₄)aralkyl in which anaromatic ring bears at least one substituent selected from the groupconsisting of (C₁ -C₁₀)alkyl, (C₁ -C₁₀)alkoxy, phenoxy, benzyloxy,methylenedioxy, (C₁ -C₄)alkylthio, phenyl, halo, trihalomethyl,adamantyl, (C₁ -C₄)carboalkoxy and nitro.
 2. A method as recited inclaim 1 wherein Y is oxygen.
 3. A method as recited in claim 2 wherein Xrepresents at least two (C₁ -C₄)alkyl substituents.
 4. A method asrecited in claim 2 wherein X represents at least one halo substituent.5. A method as recited in claim 2 wherein R₁ is (C₇ -C₁₄)aralkyl bearinga (C₁ -C₁₀)alkyl substituent and R₂ is (C₄ -C₁₂)alkyl.
 6. A method asrecited in claim 2 wherein R₁ is 4-(2,2-dimethylpropyl)phenylmethyl andR₂ is (C₄ -C₁₂)alkyl.
 7. A method as recited in claim 2 wherein Xrepresents at least one substituent selected from the group consistingof (C₁ -C₄)alkyl and halo.
 8. A method as recited in claim 2 wherein thecompound is1-(n-heptyl)-1-[4(n-butyl)benzyl]-3-(2-,4-difluorophenyl)urea.
 9. Amethod as recited in claim 2 wherein the compound is1-(3,3-dimethylbutyl-1-[4-(4-(n-butyl)benzyl]-3-(4-chloro-2,6-dimethylphenyl)urea.10. The method as recited in claim 2 wherein the compound is1-(3,3-dimethylbutyl)-1-[4-(2,2-dimethylpropyl)-benzyl]-3-(4-chloro-2,6-dimethylphenyl)urea.11. A method as recited in claim 2 wherein the compound is1-(n-heptyl)-1-[4-(2,2-dimethylpropyl)phenylmethyl]-3-(2,4-difluorophenyl)urea.